Almanac A1C

N-Acetylcysteine: From Antidote to Longevity Molecule

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dr. Karunia Valeriani Japar

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Keywords: , , , , , , ,

Introduction

N-acetylcysteine (NAC) has traditionally been recognized as a hospital antidote for acetaminophen toxicity and as an inhaled or oral mucolytic agent in chronic respiratory disease, where its thiol group disrupts disulfide bonds in mucin, reduces viscosity, and facilitates airway clearance. Over subsequent decades, converging experimental and clinical data have shown that NAC’s ability to replenish intracellular cysteine and glutathione, directly scavenge reactive oxygen and nitrogen species, and modulate redox-sensitive signaling cascades extends far beyond acute toxicology and mucus regulation, positioning it as a broader cytoprotective compound relevant to chronic, low grade oxidative and inflammatory stress seen in metabolic, cardiovascular, neurodegenerative and pulmonary disorders.

In metabolic and chronic diseases, sustained oxidative stress, subclinical inflammation, and altered mucin dynamics contribute to endothelial dysfunction, insulin resistance, organ fibrosis, and heightened vulnerability to infections, all of which accelerate biological aging. By restoring redox balance, attenuating pro-inflammatory pathways, and normalizing mucus properties at barrier surfaces such as the respiratory and gastrointestinal tracts, NAC targets shared pathophysiological hubs that link cardiometabolic disease, chronic lung disease, and neuroinflammation making it an attractive candidate for preventive strategies and longevity-focused interventions.

Within this context, there is a growing rationale to reposition NAC from a narrow “antidote-mucolytic” drug toward a pleiotropic antioxidant, anti-inflammatory, and mucoregulatory supplement that can be deployed earlier in the disease continuum. For AI-driven health tech platforms that monitor longitudinal biomarkers and symptoms, NAC offers a mechanistically coherent tool to modulate oxidative stress and mucosal health in high-risk individuals, enabling data-guided personalization of dose, duration, and combination with other nutraceuticals, while leveraging its long-standing safety record in clinical practice.

Biochemistry and Pharmacology of NAC

N-acetylcysteine (NAC) is the N-acetylated derivative of the amino acid L-cysteine, characterized by a free thiol group and an acetamide moiety that improves stability and solubility compared with cysteine itself. After oral administration, NAC is absorbed in the small intestine, undergoes significant first-pass deacetylation in the intestinal mucosa and liver to yield cysteine, and achieves modest systemic bioavailability, whereas intravenous (IV) administration bypasses first-pass metabolism and results in much higher circulating NAC and cysteine levels. Inhaled NAC, delivered as a nebulized solution, acts primarily locally on the respiratory mucosa with limited systemic exposure, which is advantageous when mucolytic effects are desired without substantial systemic pharmacologic activity. Once in the circulation, NAC and its metabolites distribute widely intro extracellular fluid and tissues, including the liver and lungs, are incorporated into the cysteine pool for glutathione synthesis, and are ultimately eliminated mainly via renal excretion as inorganic sulfates and other sulfur-containing metabolites, with a relatively short plasma half-life but prolonged functional effects via glutathione replenishment [1,2,3,4].

At the biochemical level, the principal mechanisms of NAC is its role as a precursor for intracellular glutathione, supplying cysteine as the rate-limiting substrate for c-glutamlcysteine syntetase and thereby restoring or augmenting reduced glutathione pools in hepatocytes, immune cells, and other tissues under oxidative stress. Beyond glutathione replenishment, NAC’s free thiol group directly scavenges reactive oxygen and nitrogen species and reduces disulfide bonds in proteins and mucins, accounting for both its antioxidant and mucolytic actions. NAC also modulates redox-sensitive signaling pathways: by improving intracellular redox status, it can inhibit activation of nuclear factor kB (NF-kB), leading to decreased transcription of pro-inflammatory cytokines, while concurrently influencing nuclear factor erythroid 2-related factor 2 (Nrf2) and other transcriptional regulators that govern antioxidant and phase II detoxification gene expression. Through these intertwined mechanisms, glutathione biosynthesis support, direct thiol-based redox interactions, and regulation of NF-kB, Nrf2, and allied pathways-NAC exerts broad cytoprotective effects across hepatic, pulmonary, cardiovascular, and nervous systems that underpin its clinical and preventive applications [1,5,6,7].

Mucolytic and Respiratory Effects

N-acetylcysteine (NAC) exerts its mucolytic action primarily through thiol–disulfide exchange reactions targeting the cysteine-rich domains of mucin glycoproteins that form the structural backbone of airway mucus. In pathologic states, oxidative stress promotes excessive formation of disulfide cross-links between mucin monomers, generating highly elastic, viscous gels that are poorly cleared by ciliary transport and coughing, thereby predisposing to airway obstruction, atelectasis, and secondary infection. The free sulfhydryl group of NAC reduces these disulfide bonds, depolymerizes mucin oligomers, and lowers mucus viscosity and elasticity, improving mucus rheology and facilitating its mobilization and clearance from the bronchial tree. In addition to direct mucin depolymerization, NAC appears to exert “mucoregulatory” effects by attenuating oxidative and inflammatory signalling that drive goblet cell hyperplasia and overexpression of secreted mucins such as MUC5AC, further normalizing mucus quantity and composition over time [8,9,10,11].

Clinically, these properties translate into meaningful benefits in several chronic and acute respiratory conditions characterized by mucus hypersecretion and impaired clearance. In chronic bronchitis and COPD, long-term oral NAC, particularly at higher daily doses has been  associated in meta-analyses and randomized trials with reductions in the rate of moderate-to-severe exacerbations, improvements in symptoms such as cough and sputum production, and good overall tolerability, although not all individual trials show uniform benefit. Guidelines and recent reviews highlight NAC as a useful adjunct in selected COPD and chronic bronchitis phenotypes with frequent exacerbations and prominent mucus burden, rather than as a stand-alone bronchodilator or anti-inflammatory therapy. In cystic fibrosis, inhaled and oral NAC have been used to break down inspissated secretions and to disrupt bacterial biofilms, with in vitro and early clinical data suggesting enhanced clearance of Pseudomonas aeruginosa and modulation of airway inflammation, though large, definitive outcome trials remain limited [4,12,13,14].

In the setting of viral respiratory infections, experimental models of respiratory syncytial virus and influenza show that NAC reduces ROS generation, downregulates pro-inflammatory cytokines, suppresses virus-induced overexpression of MUC5AC and goblet cell hyperplasia, and can modestly inhibit viral replication in airway epithelial cells. Clinical studies in acute viral respiratory illnesses and acute respiratory distress syndromes suggest that NAC may shorten symptom duration, improve oxygenation parameters, or reduce progression to severe respiratory failure in some cohorts, although heterogeneity in dosing, timing, and patient selection limits firm conclusions and underscores the need for larger, well-controlled trials. Collectively, the mucolytic, mucoregulatory, antioxidant, and anti-inflammatory actions of NAC underpin its role as an adjunctive therapy to reduce mucus burden, exacerbation frequency, and symptom load across chronic bronchitis, COPD, cystic fibrosis, and certain viral respiratory infections [4,8,15,16].

Antioxidant and Redox-Modulating Mechanisms

Glutathione Replenishment and Intracellular Redox Buffering

The cornerstone of N-acetylcysteine’s (NAC) antioxidant mechanism resides in its capacity to serve as bioavailable cysteine donor, thereby addressing the rate-limiting substrate constraint in glutathione (GSH)) biosynthesis. Following deacetylation in the intestinal mucosa and liver, NAC-derived cysteine enters the two-step GSH synthesis pathway: first, γ-glutamylcysteine synthetase (GCS, also designated glutamate–cysteine ligase) catalyzes the ATP-dependent condensation of glutamate and cysteine to form γ-glutamylcysteine; subsequently, glutathione synthetase catalyzes the addition of glycine to generate the mature tripeptide GSH. In pathophysiological states characterized by sustained oxidative insult such as chronic inflammation, metabolic dysfunction, aging, or acute toxicological challenges, hepatic and extrahepatic GSH pools become rapidly depleted as glutathione peroxidase (GPx) consumes reduced GSH to neutralize hydrogen peroxide and lipid hydroperoxides, and as glutathione S-transferases (GSTs) conjugate GSH to xenobiotics and lipid peroxides for subsequent elimination. By replenishing cysteine availability, NAC restores the flux through GSH synthesis, enabling cells to regenerate sufficient reduced glutathione to maintain intracellular redox buffering. Experimental evidence demonstrates that systemic or local NAC administration significantly elevates hepatic, pulmonary, neural, and vascular GSH concentrations, with the magnitude of restoration correlating to NAC dose, route of administration, and baseline GSH depletion [18,19,20,21,22].

The functional significance of restored GSH pools extends beyond simple redox balance. GSH serves as the principal physiological electron donor for glutathione peroxidase isoforms (particularly GPx1 and GPx4), which catalyze the reduction of hydroperoxides (H₂O₂ and phospholipid hydroperoxides) to their corresponding alcohols and water, thereby intercepting lipid peroxidation cascades that would otherwise compromise membrane integrity. Additionally, GSH acts as a substrate for glutaredoxins and thioredoxin reductase, which support protein disulfide reduction and maintain the cellular population of reduced protein thiols essential for enzymatic activity and signal transduction. The maintenance of a reduced cytosolic and mitochondrial GSH pool thus underpins multiple layers of cellular defense against oxidative and electrophilic stress [18,23,24].

Direct Radical Scavenging and Thiol-Based Redox Reactions

Beyond its role as a GSH precursor, the free sulfhydryl (–SH) group of NAC itself possesses direct antioxidant reactivity, though with substrate specificity that is more limited than commonly appreciated. NAC can directly scavenge certain free radicals, particularly hydroxyl radicals (·OH), nitrogen dioxide radicals (·NO₂), and carbonate radical anions (CO₃·⁻), through rapid one-electron oxidation reactions that generate the NAC-derived thiyl radical (NAC-S·). The second-order reaction rate constants for these interactions are relatively high, enabling NAC to effectively compete with endogenous antioxidants when concentrations are sufficient. Interestingly, NAC’s direct reactivity with hydrogen peroxide (H₂O₂) itself is slow, which may explain why its primary antioxidant efficacy stems from GSH replenishment rather than stoichiometric radical scavenging. However, NAC’s ability to maintain a reduced intracellular milieu indirectly restrains the generation of downstream reactive species by preserving the activity of GSH-dependent enzymes and by maintaining the oxidation-sensitive cysteine proteome in a reduced state [20,23,24,25,26,27].

Mitochondrial Protection and Mitochondrial Quality Control

Mitochondria represent both the dominant cellular source of reactive oxygen and nitrogen species and a primary target organ of oxidative damage, as ROS generated at respiratory chain Complex I and Complex III can oxidize mitochondrial DNA (mtDNA), proteins, and lipids in close proximity to their sites of generation, thereby impairing electron transport efficiency and accelerating the vicious cycle of ROS production. NAC’s capacity to lower mitochondrial matrix ROS and preserve mitochondrial redox status has emerging relevance to mitochondrial quality control (MQC), a coordinated system encompassing mitochondrial dynamics (fusion and fission), mitophagy, and biogenesis. Recent mechanistic studies demonstrate that NAC protects cardiomyocytes against hydrogen peroxide-induced oxidative stress by upregulating optic atrophy 1 (OPA1), a dynamin-like GTPase that resides on the inner mitochondrial membrane and governs cristae architecture and the balance between mitochondrial fusion and fission. Under oxidative stress, decreased OPA1 expression promotes excessive mitochondrial fragmentation and facilitates spontaneous cytochrome c release from the outer cristae compartment, triggering the intrinsic apoptotic pathway. Conversely, NAC-mediated preservation of OPA1 expression maintains elongated, networked mitochondrial morphology, prevents pathological cristae remodelling, and attenuates cytochrome c efflux and subsequent caspase-9/caspase-3 activation. Moreover, OPA1-dependent enhancement of mitochondrial fusion reduces the clearance of defective mitochondria by autophagy (mitophagy), allowing cells to selectively retain high-quality, functionally intact mitochondria; this selective retention contrasts with excessive mitophagy, which can deplete the mitochondrial pool and compromise ATP production in energy-demanding tissues. Through these OPA1-mediated mechanisms, NAC supports mitochondrial homeostasis, preserves ATP synthesis capacity, and suppresses oxidative stress-triggered apoptosis in cardiomyocytes, a finding with potential implications for ischemia or reperfusion injury, heart failure and metabolic disease [25,28,29].

In the nervous system, NAC’s benefits for mitochondrial function become particularly salient, as neurons maintain extraordinarily high ATP demands and rely heavily upon mitochondrial oxidative phosphorylation. Preclinical studies in aged neuronal preparations show that NAC pretreatment restores Complex I electron transport activity in synaptic mitochondria, lowers matrix ROS production, reduces markers of protein nitration and lipid peroxidation, and attenuates age-associated declines in GSH/GSSG ratio. These findings suggest that NAC may help preserve neuroenergetics and mitigate mitochondrial dysfunction that accumulates during the aging process and in neurodegenerative diseases [29].

Nrf2/ARE Signaling and Transcriptional Antioxidant Gene Upregulation

At the transcriptional level, NAC modulates redox-sensitive signaling cascades that orchestrate the cellular antioxidant and detoxification response through the nuclear factor erythroid 2–related factor 2 (Nrf2) and antioxidant response element (ARE) signalling axis. Under basal conditions, the transcription factor Nrf2 remains sequestered in the cytoplasm through binding to Kelch-like ECH-associated protein 1 (Keap1), a substrate adaptor for cullin-3-based ubiquitin ligase complexes that target Nrf2 for proteasomal degradation. Upon exposure to oxidative or electrophilic stress, cysteine residues in Keap1 become oxidized or covalently modified, leading to disruption of the Keap1–Nrf2 interaction, release of Nrf2, phosphorylation of Nrf2 by kinases such as protein kinase C, and subsequent translocation of Nrf2 into the nucleus. Once nuclear, Nrf2 heterodimerizes with small Maf proteins and binds to ARE sequences upstream of target genes, thereby activating transcription of more than 250 genes encoding phase II detoxification enzymes, antioxidant enzymes, and proteins involved in anti-inflammatory and mitochondrial protective pathways [19,30,31].

By improving intracellular redox status and maintaining GSH availability, NAC promotes sustained activation of the Nrf2/ARE pathway, leading to upregulation of key target genes including γ-glutamylcysteine synthetase heavy chain (GCLC) and light chain (GCLM), thus establishing a positive feedback loop to sustain GSH biosynthesis as well as NAD(P)H quinone oxidoreductase 1 (NQO1), lutathione S-transferases (GSTs), heme oxygenase-1 (HO-1), and superoxide dismutase (SOD) isoforms. Clinical and experimental evidence indicates that NAC treatment significantly increases Nrf2 mRNA expression and upregulates downstream antioxidant enzyme activities (catalase, SOD, glutathione peroxidase), thereby amplifying cellular antioxidant defenses beyond what NAC alone provides. This transcriptional upregulation is particularly important in chronically stressed tissues, as it enables sustained, endogenous synthesis of antioxidant machinery to combat ongoing oxidative insult [19,30,31].

NF-kB Inhibition and Anti-Inflammatory Signaling

Complementing its Nrf2-activating effects, NAC also modulates the inflammatory transcription factor nuclear factor κB (NF-κB), a redox-sensitive heterodimer that drives expression of pro-inflammatory cytokines, chemokines, adhesion molecules, and inducible enzymes (iNOS, COX-2) when activated. Under inflammatory or oxidative conditions, IκB kinase (IKK) becomes activated and phosphorylates the inhibitory protein IκBα, leading to its polyubiquitination and proteasomal degradation, thereby releasing the p65/p50 NF-κB dimer for nuclear translocation and gene activation. By maintaining a more reduced intracellular environment, NAC limits the oxidation of critical cysteine residues in IKK and NF-κB signalling proteins that are required for full kinase activity and DNA binding. Additionally, NAC can indirectly suppress NF-κB activation by reducing mitochondrial ROS, which are potent signalling molecules that propagate upstream IKK activation through oxidative modification of tyrosine and cysteine residues. In activated immune cells and inflamed tissues, this dual mechanism which are direct modulation of redox-sensitive kinases and reduction of ROS-dependent signalling will result in attenuated NF-κB-mediated transcription of IL-1β, TNF-α, IL-6, and other pro-inflammatory mediators [1,20].

Redox Regulation of the Cysteine Proteome and Cell Signaling

Emerging evidence underscores the importance of protein cysteine residues as redox-sensitive molecular switches that regulate enzyme activity, protein–protein interactions, and signal transduction. The “cysteine redox proteome”, encompassing proteins with reactive cysteines that undergo reversible oxidation to disulfide bonds or irreversible modification to sulfenic, sulfinic, or sulfonic acid that rogressively becomes increasingly oxidized with advancing age and chronic disease, compromising protein function and cellular signaling fidelity. By maintaining elevated intracellular cysteine and glutathione pools, NAC preserves the reduced state of vulnerable cysteine residues in signaling proteins, catalytic enzymes, and transcription factors, thereby sustaining their biological activity and redox-dependent regulatory capacity. This mechanism may be particularly relevant to aging-associated loss of cellular plasticity and stress resilience [2,24].

Implication for Aging, Neurodegeneration, and Cardiometabolic Disease

The integrative antioxidant, redox-modulating, and mitochondrial-protective actions of NAC converge on shared pathophysiological drivers of aging and chronic disease. In neurodegenerative conditions such as Alzheimer’s disease and Parkinson’s disease, the accumulation of misfolded proteins (amyloid-β, α-synuclein), impaired protein quality control, and mitochondrial dysfunction create a self-perpetuating cycle of ROS generation, lipid and protein oxidation, and neuroinflammation. Preclinical studies demonstrate that long-term NAC administration before symptom onset reduces cerebral oxidative damage markers, preserves synaptic density and neurotransmitter function, enhances Nrf2-dependent antioxidant enzyme expression in hippocampus and cortex, and attenuates cognitive decline in transgenic disease models. In cardiometabolic conditions, including obesity, insulin resistance, type 2 diabetes and atherosclerotic cardiovascular disease, dysregulated mitochondrial function, endoplasmic reticulum stress, and chronic low-grade inflammation generate excessive ROS that impairs endothelial nitric oxide synthase function, reduces NO bioavailability, and promotes atherosclerotic plaque progression. NAC’s capacity to restore mitochondrial dynamics via OPA1-mediated pathways, lower vascular ROS, and upregulate vascular antioxidant enzymes (particularly SOD and catalase) creates conditions for improved endothelial function, reduced oxidative LDL modification, and attenuation of vascular stiffness. Similarly, in the pancreatic β-cell, NAC improves insulin secretory function and preserves β-cell mass by reducing intracellular ROS and suppressing oxidative stress-triggered apoptosis. Across these diverse disease contexts, the mechanistic substrate is consistent: restoration of redox balance, activation of adaptive antioxidant gene programs via Nrf2/ARE signalling, suppression of NF-κB-driven inflammation, and preservation of mitochondrial quality control collectively attenuate oxidative damage and inflammaging that accelerate biological aging and chronic disease progression [1,20,24,25,30].

Anti-Inflammatory and Immunomodulatory Actions

Downregulation of Pro-Inflammatory Cytokines

N-acetylcysteine (NAC) exerts potent anti-inflammatory effects through its capacity to suppress the production and secretion of key pro-inflammatory cytokines that orchestrate and amplify inflammatory cascades in diverse tissue contexts. In vitro studies using lipopolysaccharide (LPS)-stimulated macrophages and monocytes demonstrate that NAC treatment significantly reduces the release of tumor necrosis alpha (TNF-a), interleukin-1b (IL-1b), and interleukin-6 (IL-6), three central mediators of innate immune activation and systemic inflammation. These effects have been corroborated in clinical settings, where administration of NAC to patients with severe inflammatory conditions including sepsis, acute respiratory distress syndrome, and COVID-19, resulted in measurable reductions in circulating TNF-a, IL-1b, and IL-6 levels alongside clinical stabilization. The multi-dimensional cytokine-suppressive actions of NAC are particularly relevant in conditions characterized by dysregulated or excessive inflammatory responses, where early attenuation of pro-inflammatory mediator release can interrupt positive feedback loops that otherwise perpetuate tissue injury [1,32,33,34].

Beyond the classical triad of TNF-a, IL-1b, and IL-6, NAC influences additional cytokines and chemokines that regulate immune cell recruitment and activation. Experimental evidence indicates that NAC reduces secretion of interleukin-8 (IL-8/CXCL8), a potent neutrophil chemoattractant, from activated macrophages and epithelial cells, potentially limiting the excessive neutrophilic infiltration seen in chronic airway inflammation and acute lung injury. NAC has also been shown to suppress interleukin-18 (IL-18), a cytokine that bridges innate and adaptive immunity by enhancing interferon-gamma (IFN-g) production from natural killer (NK) cells and T lymphocytes, thereby dampening the amplification of type 1 inflammatory responses in chronic obstructive pulmonary disease (COPD) and other conditions. The capacity of NAC to simultaneously target multiple cytokine axes underscores its broad immunomodulatory profile and positions it as an adjunctive agent in inflammatory disorders where conventional single-target therapies provide incomplete control [33,35,36,37].

Inhibition of NF-kB Activation

At the molecular level, the anti-inflammatory actions of NAC converge on the inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), a master transcription factor that governs the expression of genes encoding pro-inflammatory cytokines, chemokines, adhesion molecules, and inducible enzymes such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Under basal conditions, NF-κB dimers (typically p65/p50) are sequestered in the cytoplasm through binding to inhibitory IκB proteins; upon stimulation by pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), or pro-inflammatory cytokines, IκB kinase (IKK) becomes activated and phosphorylates IκBα, leading to its polyubiquitination and proteasomal degradation, thereby releasing NF-κB for nuclear translocation and target gene activation. Reactive oxygen species (ROS) serve as critical second messengers in this cascade, as oxidation of cysteine residues in upstream kinases and NF-κB subunits enhances DNA binding and transcriptional activity [1,38,39].

NAC blocks this pathway at multiple levels. By restoring intracellular glutathione (GSH) pools and directly scavenging ROS, NAC maintains a more reduced cellular environment that suppresses the oxidation-dependent activation of IKK and limits the ROS-mediated enhancement of NF-κB DNA binding. Experimental studies in LPS-stimulated human umbilical vein endothelial cells (HUVECs), bone marrow stromal cells (BMSCs), and primary macrophages consistently show that NAC pretreatment inhibits TNF-α-induced nuclear translocation of the p65 subunit of NF-κB and reduces the transcription of downstream target genes. In cardiomyocytes, NAC treatment weakens NF-κB signaling pathway activity, limiting the development of myocardial low-grade inflammation and increasing the expression of cardioprotective factors. These observations establish NF-κB inhibition as a central mechanistic node through which NAC exerts broad anti-inflammatory and cytoprotective effects across endothelial, cardiac, pulmonary, and immune cell populations [1,34].

Suppression of NLRP3 Inflammasome Activation

Beyond transcriptional regulation via NF-kB, NAC modulates the NLRP3 inflammasome, a cytosolic multiprotein complex that functions as a key sensor of cellular stress and driver of sterile inflammation. The NLRP3 inflammasome comprises the pattern recognition receptor NLRP3 (NOD-, LRR-, and pyrin domain containing protein 3), the adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD), and the effector protease pro-cascpase-1. Upon activation by diverse stimuli, including potassium efflux, mitochondrial ROS, lysosomal destabilization, and intracellular crystals, NLRP3 oligomerizes and recruits ASC, leading to assembly of ASC specks and auto-activation of caspase-1, which in turn cleaves pro-IL-1b and pro-IL-18 into their mature, secreted forms and initiates pyroptotic cell death through cleavage of gasdermin D (GSDMD) [40,41,42,43].

NAC inhibits NLRP3 inflammasome activation through multiple convergent mechanisms. By scavenging mitochondrial ROS, NAC prevents the upstream ROS-dependent signal required for NLRP3 assembly. Studies in LPS-primed macrophages and bone marrow stromal cells demonstrate that NAC downregulates the expression of NLRP3, ASC, and caspase-1 at both mRNA and protein levels, limiting the pool of inflammasome components available for assembly. NAC also modulates the thioredoxin-interacting protein (TXNIP)/ thioredoxin (TRX) axis: under oxidative stress, TXNIP dissociates from TRX and binds directly to NLRP3, promoting inflammasome oligomerization; by preserving TRX activity and reducing TXNIP dissociation, NAC suppresses this pro-inflammatory pathway. Consequently, NAC treatment results in marked reductions in mature IL-1b and IL-18 secretion, attenuating the inflammatory cascade triggered by inflammasome activation. These effects are particularly relevant to metabolic and age-related diseases, where NLRP3-driven sterile inflammation contributes to insulin resistance, endothelial dysfunction, and neuroinflammation [35,37].

Modulation of Immune Cell Function

NAC exerts complex, context-dependent effects on the function of both innate and adaptive immune cells. In neutrophils, NAC modulates the oxidative burst, the rapid release of ROS upon activation by reducing superoxide anion and hydrogen peroxide production in response to stimuli such as formyl-methionyl-leucyl-phenylalanine (fMLP) and phorbol myristate acetate (PMA). This attenuation of the respiratory burst can limit collateral oxidative tissue damage during exuberant neutrophilic inflammation, as seen in COPD, acute lung injury, and ischemia–reperfusion injury. Additionally, NAC reduces neutrophil chemotaxis and the release of elastase, a protease implicated in extracellular matrix destruction and emphysema progression, after prolonged administration in vivo. These effects are dose- and time-dependent, with acute high-concentration exposures producing more pronounced suppression of neutrophil function than lower doses, which may require extended treatment to alter cellular thiol status [35,36,44,45].

In lymphocytes, NAC displays biphasic immunomodulatory properties that depend on concentration and the activation state of the cells. At moderate concentrations (0.4–3.2 mM), NAC enhances T-cell proliferation, upregulates activation markers (CD25, CD71), and augments production of both pro-inflammatory (IFN-γ) and regulatory (IL-10) cytokines in response to allogeneic or mitogenic stimulation. This immunostimulatory effect may reflect NAC’s capacity to optimize the intracellular redox environment required for effective T-cell receptor signalling and metabolic reprogramming during activation. Conversely, at high concentrations (12.5–50 mM), NAC suppresses lymphocyte proliferation and dendritic cell maturation, likely through interference with redox-sensitive signalling kinases or depletion of cellular ATP. These concentration-dependent effects reconcile conflicting reports in the literature and underscore the importance of dose optimization when deploying NAC for immunomodulatory purposes in clinical or preventive settings [46,47].

Implications for Chronic Low-Grade Inflammation in Metabolic Syndrome, Obesity, and Inflammaging

Chronic low-grade inflammation often termed “metaflammation” or “inflammaging” represents a shared pathophysiological substrate linking obesity, metabolic syndrome, type 2 diabetes, cardiovascular disease, and biological aging. In obesity, hypertrophied adipocytes release pro-inflammatory adipokines (TNF-a, IL-6, leptin) and free fatty acids that activate resident macrophages, which in turn secrete additional cytokines that perpetuate local and systemic inflammation. This inflammatory milieu activates stress kinases such as c-Jun N-terminal kinase (JNK) and IKKb, which phosphorylate insulin receptor substrate-1 (IRS-1) at inhibitory serine residues and impair downstream phosphoinositide 3-kinase (PI3K)/AKT signaling, leading to insulin resistance. Concurrently, NF-kB mediated transcription of adhesion molecules and chemokines in endothelial cells promotes monocyte recruitment and atherogenesis, linking metabolic inflammation to cardiovascular risk [34,39,48,49,50,51,52].

NAC intervenes at multiple nodes of this pathogenic network. By restoring GSH pools and reducing ROS-mediated activation of NF-kB and JNK, NAC suppresses adipose tissue inflammation and improves insulin sensitivity in preclinical models of diet induced obesity and metabolic syndrome in vitro studies in 3T3-L1 adipocytes show that NAC inhibits lipid accumulation and downregulates adipogenic transcription factors such as peroxisome proliferator-activated receptor gamma (PPARg) and CCAAT/enhancer-binding protein beta (C/EBPb), while augmenting the PI3K/AKT pathway to improve insulin signaling. In rodent models of high-fat diet induced obesity, NAC administration reduces circulating TNF-α and IL-6 levels, attenuates hepatic steatosis, and improves glucose tolerance. Clinical pilot studies in patients with metabolic syndrome suggest that oral NAC supplementation may reduce markers of oxidative stress and inflammation, though larger randomized trials are needed to confirm these benefits [34,52,53].

In chronic respiratory diseases such as COPD and bronchiectasis, NAC’s combined anti-inflammatory and antioxidant actions address the oxidant-antioxidant imbalance and neutrophil-driven inflammation that underlie disease progression. By limiting NF-kB activation in airway epithelial cells and alveolar macrophages, NAC reduces the transcription of IL-8 and other neutrophil chemo attractants, potentially attenuating the cycle of neutrophil recruitment, protease release, and tissue destruction [4,10].

The concept of “inflammaging” describes the chronic, sterile, low-grade inflammation that accompanies advancing age and predisposes to age-related diseases including neurodegeneration, sarcopenia, and cardiovascular disease. Mechanistically, inflammaging arises from accumulated cellular damage, mitochondrial dysfunction, senescent cell secretory phenotypes, and dysregulated innate immune activation. NAC’s capacity to restore redox balance, suppress NF-κB and NLRP3 inflammasome activation, and modulate immune cell function positions it as a candidate intervention to mitigate the inflammatory component of biological aging. While direct clinical evidence in aging populations remains limited, the convergence of mechanistic data supports further investigation of NAC as an adjunct to lifestyle interventions aimed at reducing inflammaging and extending health span [1,34,50,51].

NAC in Metabolic Health and Longevity

N-acetylcysteine (NAC) has emerged as a candidate adjunct therapy for metabolic syndrome and cardiometabolic disease because its antioxidant and anti-inflammatory actions intersect directly with key drivers of insulin resistance, endothelial dysfunction, dyslipidemia, and mitochondrial impairment. Experimental hyperglycemia models show that NAC prevents the development of acute insulin resistance in skeletal muscle by suppressing oxidative stress, normalizing protein carbonyl levels, and preserving insulin-stimulated glucose disposal, supporting a causal role of redox imbalance in glucose intolerance. In rodent and cellular models of diet-induced obesity and metabolic disturbance, NAC restores dysregulated glucose and lipid metabolism, attenuates hepatic steatosis, reduces circulating TNF-a and IL-6, and improves insulin signaling through enhanced PI3K-AKT activity and suppression of stress kinases. Small clinical trials in humans with metabolic syndrome and polycystic ovary syndrome report that oral NAC improves insulin sensitivity indices, lowers high-sensitivity C-reactive protein, and favorably modulates fasting glucose, triglycerides, and waist circumference, suggesting translational relevance of these mechanisms [1,54,55,56,57,58,59].

Endothelial dysfunction, characterized by reduced nitric oxide (NO) bioavailability, increased adhesion molecule expression, and heightened oxidative burden, is a central pathway linking metabolic disease to atherosclerosis and vascular aging. In animal models of diabetes and chronic anemia, NAC supplementation or other ROS scavenging strategies restore endothelium-dependent vasodilation, improve acetylcholine-mediated flow responses, and reduce vascular ROS and myeloperoxidase-driven oxidative injury. In human umbilical vein endothelial cells exposed to oxidized LDL, NAC significantly lowers intracellular ROS and lipid peroxidation, preserves mitochondrial membrane potential, restores endothelial NO synthase expression, and downregulates LOX-1, ICAM-1, and VCAM-1, thereby mitigating endothelial inflammation and cholesterol accumulation that drive plaque initiation. These data support the concept that NAC may help stabilize vascular homeostasis in high-risk cardiometabolic states by simultaneously enhancing antioxidant defences and dampening inflammatory activation at the endothelial interface [39,60,61,62,63].

Mitochondrial dysfunction and impaired cellular energetics are increasingly recognized as hallmarks of both cardiometabolic disease and biological aging. By replenishing mitochondrial glutathione and scavenging mitochondrial ROS, NAC helps preserve electron transport chain integrity, maintain membrane potential, and prevent the release of pro-apoptotic factors. In aged mice, dietary supplementation with the combination of NAC and glycine (GlyNAC) raises tissue glutathione levels, reduces cardiac oxidative stress and inflammatory cytokines, upregulates genes involved in Krebs cycle and oxidative phosphorylation, and improves diastolic function, highlighting the importance of correcting glutathione deficiency to reserve age-related mitochondrial decline. Complementary in vitro work in oligodendrocytes and other cell types demonstrates that NAC reserves mitochondrial dysfunction induced by inflammatory or metabolic insults, restoring ATP production from both carbohydrate and fatty acid substrates, which is critical for tissues with high energy demands [25,58,63,64].

Viewed through contemporary longevity frameworks, NAC can be conceptually positioned as a pleiotropic modulator of three interconnected axes: redox balance, mitochondrial health, and inflammaging. On the redox axis, NAC replenishes glutathione pools and supports Nrf2-dependent transcription of antioxidant and phase II detoxification enzymes, thereby buffering oxidative damage to DNA, proteins and lips that accumulates with age.  On the mitochondrial axis, NAC safeguards mitochondrial dynamics and quality control limits ROS-induced mtDNA damage, and particularly in combination with glycine, supports mitochondrial biogenesis and substrate flexibility, properties that align with efforts to maintain metabolic resilience over the lifespan. On the inflammaging axis, NAC attenuate NF-kB and NLRP3 inflammasome activation, reduces circulating inflammatory mediators such as CRP, TNF-a, and IL-6, and modulates neutrophil and macrophage function, thereby helping to quell the chronic low-grade inflammation that underlies many age-related pathologies. Within a nutraceutical portfolio, NAC complements other longevity-focused agents such as alpha-lipoic acid, coenzyme Q10, and polyphenols by acting as glutathione-boosting thiol donor and redox buffer that can synergize with mitochondrial and anti-inflammatory interventions, though optimal dosing, long-term safety, and combinatorial strategies still require rigorous clinical evaluation [1,30,34,58,64,65,66,67,68].

Nutritional Supplementation: Dosing, Synergy, and Formulation

Oral Dosing Ranges and Bioavailability Considerations

N-acetylcysteine (NAC) is administered by oral, intravenous, and inhaled routes, with oral supplementation being the predominant mode in preventive health and longevity contexts. Following oral ingestion, NAC undergoes rapid intestinal absorption but extensive first-pass deacetylation in the intestinal mucosa and liver, directing most of the released cysteine toward hepatic glutathione (GSH) synthesis rather than systemic circulation. As a consequence, absolute oral bioavailability of intact NAC is relatively low, estimated at approximately 6–10% for total NAC and 4–9% for the reduced form, with peak plasma concentrations (Cmax) occurring between one and two hours post-ingestion. Despite limited systemic bioavailability of the parent compound, the functional outcome, elevation of tissue glutathione, is robust, a cysteine derived from NAC enters cells and supports GSH biosynthesis in liver, lung, heart, and other organs [1,69,70].

The typical oral dosing range for NAC in clinical and supplemental use spans from 600 mg to 1,800 mg per day, divided into one to three doses. For respiratory conditions such as chronic bronchitis and COPD, the licensed dose in many countries is 600 mg/day, though clinical trials frequently employ 1,200 mg/day or higher to achieve greater mucolytic and antioxidant effects. In metabolic and longevity-oriented supplementation, doses of 1,200 mg/day have been used safely in clinical trials lasting several weeks to months, with studies documenting tolerability at doses up to 3,000 mg/day in respiratory disease populations. The Dutch National Institute for Public Health and the Environment (RIVM) concluded that adults can consume up to a maximum of 1,200 mg NAC per day from food supplements without exceeding known therapeutic thresholds, supporting the safety of this dose ceiling for preventive use [1,4,69].

Pharmaceutical versus Over-the-Counter Formulations

NAC is available in several pharmaceutical formulations, including oral solutions, effervescent tablets, standard oral tablets, and capsules, as well as intravenous and inhalation preparations for hospital use. Effervescent tablets, when dissolved in water, provide a flavored solution that is generally better tolerated than the sulfurous-tasting oral liquid formulation; pharmacokinetic studies demonstrate bioequivalence between effervescent and oral solution NAC, with equivalent Cmax and area-under-the-curve (AUC) values when matched for dose. Subjects in comparative trials preferred effervescent tablets in terms of taste, flavour, texture, and overall likeability, which may improve adherence for long-term supplementation [1,71].

The regulatory status of NAC as a dietary supplement varies by jurisdiction and has been subject to evolving interpretation. In the United States, the FDA has determined that NAC is excluded from the statutory definition of a dietary supplement because it was approved as a drug (for acetaminophen overdose) prior to its marketing as a supplement. However, the FDA has expressed willingness to exercise enforcement discretion for NAC-containing products labeled as dietary supplements that would otherwise be lawfully marketed, and is considering rulemaking to formally permit NAC in supplements. In Europe and other regions, NAC is widely available both as a registered mucolytic medicine and as an over-the-counter supplement, with recommended daily doses in supplements typically ranging from 200 mg to 2,000 mg. These distinctions are relevant for clinicians and consumers navigating product selection: pharmaceutical-grade NAC formulations are manufactured under stricter quality controls (Good Manufacturing Practice for medicines), whereas dietary supplement formulations may vary in purity, excipients, and labelling claims [70].

Novel delivery strategies are being explored to enhance NAC bioavailability. N-acetylcysteine ethyl ester (NACET), an esterified prodrug, exhibits greater lipophilicity, improved cellular uptake, and more efficient conversion to cysteine than standard NAC, resulting in enhanced glutathione elevation in preclinical studies. Clinical trials comparing standard NAC, NACET, and combination formulations (NACET plus glycine, selenium, and molybdenum) are underway to characterize the pharmacokinetic profiles of these next-generation formulations and guide future recommendations for routine preventive use [72].

Synergistic Use with Glutathione, Selenium, and Vitamin C

The antioxidant network operates through interconnected cycles in which individual nutrients regenerate and amplify one another’s activity, creating synergy that exceeds the sum of isolated effects. NAC occupies a central position in this network as the primary cysteine donor for glutathione synthesis; by supplying the rate-limiting amino acid for GCS-catalyzed γ-glutamylcysteine formation, NAC enables cells to manufacture glutathione on demand rather than relying on exogenous GSH, which is poorly absorbed intact. When combined with direct glutathione supplementation, particularly liposomal glutathione formulations designed to enhance absorption, NAC can both replenish depleted GSH pools and sustain ongoing synthesis, providing layered antioxidant coverage [1,73].

Selenium is an essential trace mineral that serves as a cofactor for the selenoenzyme glutathione peroxidase (GPx), which catalyzes the reduction of hydrogen peroxide and lipid hydroperoxides using GSH as the electron donor. Without adequate selenium, GPx activity is impaired regardless of GSH availability, limiting the functional output of the glutathione system. Co-supplementation of NAC with selenium ensures that both the substrate (GSH, via NAC-derived cysteine) and the enzymatic machinery (GPx, via selenium) are optimized, producing a synergistic enhancement of peroxide detoxification and protection against lipid peroxidation. Commercial formulations combining NAC with selenium and molybdenum (a cofactor for sulfite oxidase involved in sulfur amino acid metabolism) leverage this biochemical rationale to maximize antioxidant and detoxification efficiency [73,74].

Vitamin C (ascorbic acid) complements NAC through its capacity to regenerate oxidized glutathione (GSSG) back to its reduced, active form (GSH), thereby extending the functional lifespan of the glutathione pool. Vitamin C also directly scavenges aqueous-phase free radicals, sparing GSH for other protective reactions and enhancing overall cellular antioxidant capacity. Conversely, glutathione can regenerate oxidized vitamin C (dehydroascorbate) back to ascorbate, establishing a bidirectional recycling loop that sustains both antioxidants. Combination products pairing NAC with buffered vitamin C are designed to exploit this mutual regeneration, providing synergistic protection against oxidative stress in immune, hepatic, and cardiovascular tissues.

Synergy with Alpha-Lipoic Acid and Other Antioxidants

Alpha-lipoic acid (ALA) is a unique amphipathic antioxidant capable of operating in both aqueous and lipid compartments, directly scavenging ROS, chelating redox-active metals, and regenerating other antioxidants including glutathione, vitamin C, vitamin E, and coenzyme Q10. ALA also upregulates endogenous GSH synthesis by enhancing cysteine uptake and activating the Nrf2/ARE pathway, effects that parallel and reinforce those of NAC. The combination of NAC and ALA has been incorporated into comprehensive liver-support and detoxification formulas, where both agents contribute to phase II conjugation reactions (via GSH and glutathione S-transferases) and protect hepatocytes from oxidative and inflammatory injury.  However, context matters: one preclinical study in mild colitis found that while NAC alone exhibited strong colonic antioxidant and anti-inflammatory activity, the combination of ALA plus NAC paradoxically increased hepatic pro-inflammatory cytokines and transaminases, highlighting the need for careful dose optimization and clinical validation of combination regimens [74].

Coenzyme Q10 (ubiquinone/ubiquinol), another endogenous antioxidant concentrated in mitochondria, works in concert with NAC to preserve electron transport chain function and limit mitochondrial ROS generation, polyphenols such as resveratrol and quecertin provide additional anti-inflammatory and sirtuin-activating effects that complements NAC’s redox-modulating actions. Formulations marketed for “antioxidant synergy” often combine NAC (or its precursor role for GSH) with ALA, vitamin C, vitamin E complex, coenzyme Q10, selenium and polyphenols, aiming to cover water-soluble, lipid soluble, and mitochondrial antioxidant compartments simultaneously [73].

GlyNac: Glycine plus NAC for Longevity

One of the most compelling synergistic strategies involving NAC is its combination with glycine, collectively termed GlyNAC. Glycine is the third amino acid consistent of the glutathione tripeptite (γ-glutamyl-cysteinyl-glycine); although glycine is generally abundant, emerging evidence suggest that older adults may have suboptimal glycine availability for GSH synthesis, particularly under conditions of oxidative or metabolic stress. Randomized controlled trials in older humans demonstrate that 16-24 seeks of GlyNAC supplementation (typically 100 mg/kg/day glycine plus 100 mg/kg/day NAC, or approximately 7 g each for a 70-kg adult) corrects intracellular GSH deficiency, lowers oxidative stress markers, improves mitochondrial fatty acid oxidation, reduces insulin resistance and inflammation, and enhances physical function measures including gait speed, grip strength, and six-minute walk distance. Remarkably, GlyNAC supplementation also improved multiple hallmarks of aging, mitochondrial dysfunction, genomic damage, cellular senescence, stem cell fatigue, and altered nutrient sensing toward levels observed in younger adults. These findings position GlyNAC as a promising, simple and well-tolerated intervention for promoting healthy aging, with the “Power of 3” hypothesis proposing that the combined effects of glycine, cysteine (from NAC), and glutathione together drive the observed multi-system benefits [75,76].

Practical Considerations for Metabolic and Liver Health

For individuals seeking metabolic and hepatic supports, NAC is frequently combined with milk thistle (silymarin), ALA, selenium, B-vitamins, and other botanicals in comprehensive liver-support formulas. Milk thistle provides hepatoprotective flavonolignans that stabilize hepatocyte membranes and support phase I and phase II detoxification, while NAC supplies cysteine for GSH synthesis and ALA regenerates multiple antioxidants and enhances insulin sensitivity. Selenium as selenomethionine or high-selenium yeast (SelenoExcell) supports glutathione peroxiedase activity, and choline supports hepatic lipid metabolism. Clinical studies in patients with non-alcoholic fatty liver disease (NAFLD) report that three months of oral NAC supplementation reduces alanine aminotransferase (ALT) levels and spleen size, a surrogate marker of hepatic congestion, consistent with improvement in fatty infiltration. These data support the inclusion of NAC with multi-nutrient protocols aimed at optimizing liver function, detoxification capcity and metabolic resilience, particularly in populations at risk for or diagnosed with metabolic-associated fatty liver disease [77,78].

Safety Profile, Adverse Effects, and Contraindications

N -acetylcysteine (NAC) has an extensive safety record across oral, intravenous, and inhaled routes, with most adverse effects being mild and dose-related. Oral NAC is generally well tolerated at doses used for respiratory and supplemental indications; the most frequent side effects are gastrointestinal, including nausea, vomiting, diarrhea, flatulence, epigastric discomfort, and gastroesophageal reflux, reported in roughly 10–25% of patients in clinical series and often mitigated by dose splitting or taking with food. Intravenous NAC, particularly high-dose loading regimens for acetaminophen overdose, carries a higher risk of rate-related anaphylactoid reactions—pruritus, flushing, urticaria, angioedema, bronchospasm, and hypotension—occurring in up to 18% of patients, though most are mild to moderate and respond to temporary infusion interruption, antihistamines, and, if needed, corticosteroids, with severe reactions such as bronchospasm and circulatory collapse being rare (~1%). Inhaled NAC used as a mucolytic can provoke cough, throat irritation, bronchospasm, chest tightness, and oral or nasal irritation; meta-analytic data suggest higher rates of airway-related adverse events than with oral NAC, which is clinically relevant in patients with hyperreactive airways or severe asthma. Overdose or major dosing errors with IV NAC can produce serious toxicity, including hemolysis, thrombocytopenia, metabolic acidosis, acute kidney injury, cerebral edema, and rarely death, underscoring the importance of weight-based dosing and infusion protocols in hospital settings [1,79,80,81].

With respect to special populations, available human data and regulatory assessments indicate that NAC is not associated with major teratogenic or fetotoxic effects at therapeutic doses, and it is widely used in pregnant women for acetaminophen poisoning and as a mucolytic. StatPearls and other reviews note no clear evidence of fetal harm in pregnancy; dosing typically mirrors non-pregnant protocols, although use should be restricted to clear indications and under medical supervision. For lactation, systemic exposure of breastfed infants to NAC after maternal oral or inhaled therapy appears low, but some authorities advise pumping and discarding milk for approximately 30 hours after high-dose IV therapy to minimize exposure; standard-dose oral or inhaled NAC is generally considered acceptable when benefits outweigh theoretical risks. Toxicology-based risk assessments for NAC in food supplements, including evaluations by the Norwegian Scientific Committee for Food and Environment and the Dutch RIVM, conclude that daily supplemental intakes up to 1,200 mg (and lower doses such as 50 mg/day in women of childbearing age) do not raise toxicological concerns and remain well below therapeutic mucolytic doses [79].

NAC reduces collagen-, ADP-, and thromboxane-induced platelet aggregation in a concentration- and time-dependent manner by restoring the reduced form of human serum albumin and modulating arachidonic acid metabolite synthesis (decreasing thromboxane B₂ and increasing anti-aggregant prostaglandin D₂). Clinical work in vascular surgery patients suggests that NAC has mild anticoagulant and platelet-inhibiting properties that may prolong bleeding time and alter laboratory coagulation parameters, which should be considered when NAC is combined with antiplatelet agents (aspirin, clopidogrel) or anticoagulants, although one study found that large doses of NAC did not reverse clopidogrel’s antiplatelet effect. Conversely, emerging data indicate that NAC may prevent arterial thrombosis and exert thrombolytic effects by reducing the size of ultra-large von Willebrand factor multimers that cross-link platelets in high-shear conditions, highlighting both potential therapeutic opportunities and bleeding risks at higher doses or in high-risk patients. Overall, while NAC is considered a low-toxicity compound with a wide therapeutic index, clinicians should exercise caution in individuals with a history of NAC-induced anaphylactoid reactions, severe asthma (for inhaled formulations), bleeding disorders, concomitant anticoagulant or antiplatelet therapy, or in settings of high-dose IV administration, and should individualize use in pregnancy and breastfeeding based on risk–benefit assessment [1,79,82,83,84,85].

Digital Health, AI, and NAC Personalization

Digital health and artificial intelligence (AI) create opportunities to move NAC from a “one-size-fits-all” supplement toward a precision, phenotype-guided intervention. Redox biology is highly individual, shaped by genetics, comorbidities, environmental exposures, diet and medication use, and recent work in “personalized redox biology” highlights the need for integrated, multivariate assessment of redox markers rather than reliance on single laboratory tests. Machine-learning models applied to panels of oxidative stress and antioxidant biomarkers such as total antioxidant capacity, glutathione status, lipid peroxidation products, and inflammatory markers, can derive latent redox “signatures” that stratify patients into subgroups with distinct oxidative phenotypes and cardiovascular risk profiles, as demonstrated by neural network-based classification using antioxidant activity indices in cardiovascular disease cohorts. Similar models could identify those with glutathione deficiency, mitochondrial oxidative stress, or inflammaging signatures most likely to benefit from NAC or GlyNAC, while simultaneously flagging individuals where aggressive antioxidant therapy might blunt beneficial stress-adaptation (mitohormesis) or interact adversely with oncologic and immune therapies [58,86,87,88].

AI-enabled clinical decision support systems that integrate medication lists, comorbidity patterns, and lab data can also optimize NAC use in the context of polypharmacy and multimorbidity. Electronic prescribing tools have already improved dosing accuracy and timeliness of NAC in acetaminophen toxicity, illustrating how algorithmic support can reduce medication errors in time-sensitive scenarios. Extending these systems to chronic care, AI models could identify patients with overlapping conditions, such as COPD plus metabolic syndrome or NAFLD plus cardiovascular disease where NAC’s mucolytic, hepatoprotective, and endothelial benefits are most synergistic, while accounting for bleeding risk, renal function, and potential drug interactions (for example concomitant antiplatelet or anticoagulant therapy). In parallel, AI can analyze longitudinal EHR data to detect real-world NAC response patterns, distinguishing clinically meaningful improvements in exacerbation rates, metabolic parameters, or quality-of-life scores from regression to the mean, and thereby refine patient-selection rules over time [1,84,88,89].

Within preventive and longevity-focused healthtech platforms, NAC can be embedded into data-driven programs that combine remote monitoring, adaptive dosing, and n-of-1 experimentation. Remote patient monitoring infrastructures already used in cardiometabolic and heart failure care, leveraging connected blood pressure cuffs, wearables, glucometers and symptoms apps can be extended NAC-responsive endpoints such as respiratory symptoms, exercise tolerance, sleep quality, heart-rate variability, and metabolic markers (glucose, triglycerides, liver enzymes). Machine-learning algorithms can then link changes in these digital and biochemical biomarkers to NAC exposure, adjusting dose, timing, or combination (for example addition of glycine, selenium, vitamin C, or alpha-lipoic acid) in an individualized, Bayesian “learn-as-you-go” fashion, akin to n-of-1 trials at scale. Over time, aggregated data from thousands of users could be used to derive and continually update evidence-based NAC prescribing pathways for specific phenotypes such as redox-dysregulated NAFLD, endothelial dysfunction in diabetes, or fatigue and dysautonomia in post-viral syndromes, transforming NAC from a generic over-the-counter antioxidant into a precisely targeted component of AI-guided longevity medicine [88,89].

Limitations of Current Evidence and Research Gaps

Despite extensive clinical use, the evidence base for n-acetylcysteine (NAC) in preventive and longevity applications is constrained by substantial methodological heterogeneity and gaps. Existing trial varies widely in dose (from 600 to 3,000 mg/day), route (oral, IV, inhaled), and formulation (standard NAC, effervescent tablets, NAC plus glycine or other nutrients), making cross-study comparison and meta-analysis difficult. Study populations are often small and highly selected (for example COPD, NAFLD, or specific neuropsychiatric disorders), with short follow up and diverse endpoints ranging from subjective symptom scores to isolated biomarkers, which limits the ability to draw robust conclusions about long-term cardiometabolic or lifespan outcomes. Preventive and longevity-focused data are particularly sparse; most trials address disease treatment or adjunctive care rather than primary prevention or health span extension, and few incorporate modern redox phenotyping or stratification by baseline glutathione status, mitochondrial function, or inflammaging markers [1,67,86].

Priority research needs include adequately powered, long-duration randomized trials evaluating chronic NAC or GlyNAC supplementation (for example ³12-24 months) with hard metabolic, cardiovascular and neurocognitive endpoints, as well as systematic monitoring for rare adverse events, effects on platelet function, and potential interactions with chemotherapy, immunotherapy or anticoagulants. Dose finding studies are required to define optimal dosing windows for metabolic syndrome, NAFLD, and neuropsychiatric indications, distinguishing between minimal effective, hermetic, and potentially excessive antioxidant doses that might interfere with adaptive stress signaling. Furthermore, combination-therapy trials that systematically test NAC with selenium, vitamin C, alpha-lipoic acid, coenzyme Q10, or lifestyle interventions (diet, exercise, time-restricted feeding) are needed to clarify additive versus synergistic effects and to determine whether multi-target antioxidant strategies translate into measurable improvements in health span or disease-free survival [1,67,73,84,90].

Conclusion

NAC emerges from the contemporary evidence base as a versatile small molecule that bridges classical pharmacology and modern preventive medicine. Through its capacity to replenish glutathione, scavenge reactive species, modulate redox-sensitive signaling, and cleave disulfide bonds in mucins, NAC combines robust antioxidant, anti-inflammatory, and mucolytic actions that are mechanistically coherent across hepatic, respiratory, cardiovascular and nervous systems. These properties underpin well-established clinical roles in acetaminophen toxicity chronic bronchitis and COPD, and selected psychiatric and hepatologic indications, while an expanding body of experimental and early clinical data supports its potential utility in insulin resistance, endothelial dysfunction, mitochondrial impairment, and other hallmarks of cardiometabolic disease and aging.

From a translational perspective, NAC is best viewed as an evidence-based drug with promising, yet still emerging applications as a nutritional and longevity focused supplement. Its generally favorable safety profile, oral bioavailability at practical doses, and synergistic interactions with glutathione, selenium, vitamin C, alpha-lipoic acid, and glycine make it an attractive candidate for inclusion in metabolic and liver support protocols, particularly in individuals with documented oxidative stress or glutathione depletion. At the same time, heterogeneity in trial designs, limited long-term outcome data, and context-dependent effects on immunity and redox signaling argue for cautious dosing, attention to comorbidities and concomitant medications (especially antiplatelet and anticoagulant agents), and avoidance in indiscriminate high-dose use in the absence of clear indications.

Looking ahead, the convergence of NAC with digital health and AI-enabled analytics offers a pathway to move beyond generic supplementation toward personalized redox and mitochondrial medicine. By integrating longitudinal clinical data, multi-omic redox phenotyping, and remote monitoring of metabolic and cardiorespiratory biomarkers, AI-driven decision support systems could help identify individuals most likely to benefit from NAC or GlyNAC, optimize dosing and combinations over time, and detect early signs of intolerance or interaction. Within such frameworks, NAC can be positioned not as a stand-alone “anti-aging pill” but as modular, mechanistically grounded tool deployed alongside lifestyle interventions and complementary nutraceuticals, with the overarching aim of extending health span while maintaining a strong commitment to evidence-based practice and safety surveillance.

Reference

  1. Tenório MC dos S, Graciliano NG, Moura FA, Oliveira ACM de, Goulart MOF. N-Acetylcysteine (NAC): Impacts on Human Health. Antioxidants [Internet]. 2021 Jun 16;10(6):967. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234027/
  2. Pedre B, Barayeu U, Ezeriņa D, Dick TP. The mechanism of action of N-acetylcysteine (NAC): The emerging role of H2S and sulfane sulfur species. Pharmacology & Therapeutics [Internet]. 2021 Jun 23;228:107916. Available from: https://pubmed.ncbi.nlm.nih.gov/34171332/
  3. Àngels Gispert-Ametller, Aguilar-Salmerón R. [Translated article] N-acetylcysteine: 50 years since the discovery of an antidote that has changed the prognosis of acetaminophen poisoning. Farmacia Hospitalaria. 2025 Nov 1;
  4. Mokra D, Mokry J, Barosova R, Hanusrichterova J. Advances in the Use of N-Acetylcysteine in Chronic Respiratory Diseases. Antioxidants [Internet]. 2023 Sep 1;12(9):1713. Available from: https://www.mdpi.com/2076-3921/12/9/1713
  5. Pedre B, Barayeu U, Ezeriņa D, Dick TP. The mechanism of action of N-acetylcysteine (NAC): The emerging role of H2S and sulfane sulfur species. Pharmacology & Therapeutics [Internet]. 2021 Jun 23;228:107916. Available from: https://pubmed.ncbi.nlm.nih.gov/34171332/
  6. Santus P, Juan Camilo Signorello, Danzo F, Lazzaroni G, Saad M, Radovanovic D. Anti-Inflammatory and Anti-Oxidant Properties of N-Acetylcysteine: A Fresh Perspective. Journal of Clinical Medicine. 2024 Jul 15;13(14):4127–7.
  7. Yahia Z, Yahia A, Abdelaziz T. N-acetylcysteine Clinical Applications. Cureus. 2024 Oct 24;
  8. Rogliani P, Manzetti GM, Gholamalishahi S, Cazzola M, Calzetta L. Impact of N-Acetylcysteine on Mucus Hypersecretion in the Airways: A Systematic Review. International Journal of Chronic Obstructive Pulmonary Disease. 2024 Oct;Volume 19:2347–60.
  9. Aldini G, Altomare A, Baron G, Vistoli G, Carini M, Borsani L, et al. N-Acetylcysteine as an antioxidant and disulphide breaking agent: the reasons why. Free radical research [Internet]. 2018;52(7):751–62. Available from: https://www.ncbi.nlm.nih.gov/pubmed/29742938
  10. Sadowska AM. N-Acetylcysteine mucolysis in the management of chronic obstructive pulmonary disease. Therapeutic Advances in Respiratory Disease. 2012 Feb 23;6(3):127–35.
  11. Gupta R, Wadhwa R. Mucolytic Medications [Internet]. PubMed. Treasure Island (FL): StatPearls Publishing; 2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK559163/
  12. Zhou Y, Wu F, Shi Z, Cao J, Tian J, Yao W, et al. Effect of high-dose N-acetylcysteine on exacerbations and lung function in patients with mild-to-moderate COPD: a double-blind, parallel group, multicentre randomised clinical trial. Nature Communications [Internet]. 2024 Sep 30;15(1). Available from: https://www.nature.com/articles/s41467-024-51079-1
  13. Nasikhatussoraya N, Hamid Faqih Umam, Ainingtyas Marda Rizkani, Santoso H. A Systematic Review and Meta-Analysis: The Long-Term Effects of Oral N-Acetylcysteine in Chronic Obstructive Pulmonary Disease. Nusantara Science and Technology Proceedings [Internet]. 2024 Oct 5 [cited 2025 Dec 2];19–25. Available from: https://nstproceeding.com/index.php/nuscientech/article/view/1271?articlesBySimilarityPage=10
  14. Papi A, Alfano F, Bigoni T, Mancini L, Mawass A, Baraldi F, et al. N-acetylcysteine Treatment in Chronic Obstructive Pulmonary Disease (COPD) and Chronic Bronchitis/Pre-COPD: Distinct Meta-analyses. Archivos De Bronconeumologia [Internet]. 2024 May 1;60(5):269–78. Available from: https://pubmed.ncbi.nlm.nih.gov/38555190/
  15. Chi L, Shan Y, Cui Z. N-Acetyl-L-Cysteine Protects Airway Epithelial Cells during Respiratory Syncytial Virus Infection against Mucin Synthesis, Oxidative Stress, and Inflammatory Response and Inhibits HSPA6 Expression. Analytical Cellular Pathology. 2022 Aug 21;2022:1–9.
  16. Schloss J, Leach M, Brown D, Hannan N, Kendall-Reed P, Steel A. The effects of N-acetyl cysteine on acute viral respiratory infections in humans: A rapid review. Advances in Integrative Medicine. 2020 Dec;7(4):232–9.
  17. Ning Lv, Huang C, Huang H, Dong Z, Chen X, Lu C, et al. Overexpression of Glutathione S-Transferases in Human Diseases: Drug Targets and Therapeutic Implications. Antioxidants. 2023 Nov 6;12(11):1970–0.
  18. Lushchak VI. Glutathione Homeostasis and Functions: Potential Targets for Medical Interventions. Journal of Amino Acids. 2012;2012:1–26.
  19. Chan KK, Han X, Yuet Wai Kan. An important function of Nrf2 in combating oxidative stress: Detoxification of acetaminophen. Proceedings of the National Academy of Sciences of the United States of America. 2001 Apr 3;98(8):4611–6.
  20. Tardiolo G, Bramanti P, Mazzon E. Overview on the Effects of N-Acetylcysteine in Neurodegenerative Diseases. Molecules [Internet]. 2018 Dec 13;23(12). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320789/
  21. Aldini G, Altomare A, Baron G, Vistoli G, Carini M, Borsani L, et al. N-Acetylcysteine as an antioxidant and disulphide breaking agent: the reasons why. Free radical research [Internet]. 2018;52(7):751–62. Available from: https://www.ncbi.nlm.nih.gov/pubmed/29742938
  22. Atkuri KR, Mantovani JJ, Herzenberg LA, Herzenberg LA. N-Acetylcysteine—a safe antidote for cysteine/glutathione deficiency. Current Opinion in Pharmacology [Internet]. 2007 Aug;7(4):355–9. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4540061/
  23. Ferreira CA, Ni D, Rosenkrans ZT, Cai W. Scavenging of reactive oxygen and nitrogen species with nanomaterials. Nano Research [Internet]. 2018 May 26 [cited 2022 Apr 1];11(10):4955–84. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233906/
  24. Martinez-Banaclocha M. N-Acetyl-Cysteine: Modulating the Cysteine Redox Proteome in Neurodegenerative Diseases. Antioxidants. 2022 Feb 18;11(2):416.
  25. Zheng J, Zhao L, Liu Y, Chen M, Guo X, Wang J. N-acetylcysteine, a small molecule scavenger of reactive oxygen species, alleviates cardiomyocyte damage by regulating OPA1-mediated mitochondrial quality control and apoptosis in response to oxidative stress. Journal of Thoracic Disease. 2024 Aug;16(8):5323–36.
  26. Meng J. An emerging role for cysteine-mediated redox signaling in aging. Redox Biology. 2025 Aug 29;86:103852–2.
  27. Murphy MP, Bayir H, Belousov V, Chang CJ, Davies KJA, Davies MJ, et al. Guidelines for measuring reactive oxygen species and oxidative damage in cells and in vivo. Nature Metabolism [Internet]. 2022 Jun 1;4(6):651–62. Available from: https://www.nature.com/articles/s42255-022-00591-z
  28. Rahmani S, Roohbakhsh A, Pourbarkhordar V, Hayes AW, Karimi G. Melatonin regulates mitochondrial dynamics and mitophagy: Cardiovascular protection. Journal of cellular and molecular medicine [Internet]. 2024 Sep;28(18):e70074. Available from: https://pubmed.ncbi.nlm.nih.gov/39333694/
  29. Zinovkin RA, Romaschenko VP, Galkin II, Zakharova VV, Pletjushkina OYu, Chernyak BV, et al. Role of mitochondrial reactive oxygen species in age-related inflammatory activation of endothelium. Aging. 2014 Aug 13;6(8):661–74.
  30. Petri S, Körner S, Kiaei M. Nrf2/ARE Signaling Pathway: Key Mediator in Oxidative Stress and Potential Therapeutic Target in ALS. Neurology Research International. 2012;2012:1–7.
  31. Rahil Jannatifar, Kazem Parivar, Nasim Hayati Roodbari, Mohammad Hossein Nasr-Esfahani. The Effect of N-Acetyl-Cysteine on NRF2 Antioxidant Gene Expression in Asthenoteratozoospermia Men: A Clinical Trial Study. PubMed. 2020 Oct 1;14(3):171–5.
  32. Hasan MJ. N-acetylcysteine in Severe COVID-19: The Possible Mechanism. International Journal of Infection. 2020 Aug 31;7(4).
  33. Djajalaksana S, Listyoko AS, Hardiyanto Rumaratu SP. Administration of N-Acetylcysteine (NAC) as Adjunctive Therapy for COVID-19 Patients by Improving Oxidative Stress and Inflammation Through Assessment of MDA, IL-6, IL-1β, TNF-α, and TGF-β. International Journal of Research and Review. 2023 Aug 11;10(8):315–23.
  34. Radomska-Leśniewska DM, Niderla-Bielińska J, Kujawa M, Jankowska-Steifer E. Targeting Metabolic Dysregulation in Obesity and Metabolic Syndrome: The Emerging Role of N-Acetylcysteine. Metabolites. 2025 Sep 26;15(10):645.
  35. Liu X, Lu X, Hu Z. N-Acetylcysteine (NAC) Inhibits Synthesis of IL-18 in Macrophage by Suppressing NLRP3 Expression to Reduce the Production of IFN-γ from NK Cells. Computational and mathematical methods in medicine. 2021 Dec 3;2021:1–10.
  36. Sadowska AM, Begoña Manuel-y-Keenoy, Vertongen T, Schippers G, Dorota Radomska-Lesniewska, Heytens E, et al. Effect of N-acetylcysteine on neutrophil activation markers in healthy volunteers: In vivo and in vitro study. Pharmacological research. 2006 Mar 1;53(3):216–25.
  37. Liu Y, Yao W, Xu J, Qiu Y, Cao F, Li S, et al. The anti-inflammatory effects of acetaminophen and N-acetylcysteine through suppression of the NLRP3 inflammasome pathway in LPS-challenged piglet mononuclear phagocytes. Innate Immunity. 2015 Jan 8;21(6):587–97.
  38. Yu H, Lin L, Zhang Z, Zhang H, Hu H. Targeting NF-κB pathway for the therapy of diseases: mechanism and clinical study. Signal Transduction and Targeted Therapy [Internet]. 2020 Sep 21;5(1):1–23. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC7506548/
  39. Shoelson SE. Inflammation and insulin resistance. Journal of Clinical Investigation [Internet]. 2006 Jul 3;116(7):1793–801. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1483173/
  40. Klaudia Sztolsztener, Wiktor Bzdęga, Katarzyna Hodun, Chabowski A. N-Acetylcysteine Decreases Myocardial Content of Inflammatory Mediators Preventing the Development of Inflammation State and Oxidative Stress in Rats Subjected to a High-Fat Diet. International Journal of Inflammation. 2023 Mar 11;2023:1–17.
  41. Zhan X, Li Q, Xu G, Xiao X, Bai Z. The mechanism of NLRP3 inflammasome activation and its pharmacological inhibitors. Frontiers in Immunology. 2023 Jan 18;13.
  42. Liu X, Lu X, Hu Z. N-Acetylcysteine (NAC) Inhibits Synthesis of IL-18 in Macrophage by Suppressing NLRP3 Expression to Reduce the Production of IFN-γ from NK Cells. Computational and mathematical methods in medicine. 2021 Dec 3;2021:1–10.
  43. Paik S, Kim JK, Silwal P, Sasakawa C, Jo EK. An update on the regulatory mechanisms of NLRP3 inflammasome activation. Cellular & Molecular Immunology. 2021 Apr 13;18(5):1141–60.
  44. Allegra L, Sasso M, Bovio C, Massoni C, Fonti E, Braga P. Human Neutrophil Oxidative Bursts and their in vitro Modulation by Different N-Acetylcysteine Concentrations. Arzneimittelforschung. 2011 Dec 26;52(09):669–76.
  45. Hirschfeld J, White PC, Milward MR, Cooper PR, Chapple ILC. Modulation of Neutrophil Extracellular Trap and Reactive Oxygen Species Release by Periodontal Bacteria. McCormick B, editor. Infection and Immunity. 2017 Dec;85(12).
  46. Karlsson H, Nava S, Mats Remberger, Hassan Z, Hassan M, Olle Ringdén. N‐acetyl‐L‐cysteine increases acute graft‐versus‐host disease and promotes T‐cell‐mediated immunity in vitro. European Journal of Immunology. 2011 Jan 24;41(4):1143–53.
  47. Omara FO, Blakley BR, Bernier J, Fournier M. Immunomodulatory and protective effects of N-acetylcysteine in mitogen-activated murine splenocytes in vitro. Toxicology. 1997 Jan;116(1-3):219–26.
  48. Yu H, Lin L, Zhang Z, Zhang H, Hu H. Targeting NF-κB pathway for the therapy of diseases: mechanism and clinical study. Signal Transduction and Targeted Therapy [Internet]. 2020 Sep 21;5(1):1–23. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC7506548/
  49. Mussbacher M, Salzmann M, Brostjan C, Hoesel B, Schoergenhofer C, Datler H, et al. Cell Type-Specific Roles of NF-κB Linking Inflammation and Thrombosis. Frontiers in Immunology [Internet]. 2019 Feb 4;10. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369217/
  50. Dali-Youcef N, Mecili M, Ricci R, Andrès E. Metabolic inflammation: Connecting obesity and insulin resistance. Annals of Medicine. 2012 Jul 26;45(3):242–53.
  51. Saltiel AR, Olefsky JM. Inflammatory mechanisms linking obesity and metabolic disease. Journal of Clinical Investigation [Internet]. 2017 Jan 3;127(1):1–4. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5199709/
  52. Dludla PV, Mazibuko-Mbeje SE, Nyambuya TM, Mxinwa V, Tiano L, Marcheggiani F, et al. The beneficial effects of N-acetyl cysteine (NAC) against obesity associated complications: A systematic review of pre-clinical studies. Pharmacological Research [Internet]. 2019 Aug 1;146:104332. Available from: https://www.sciencedirect.com/science/article/abs/pii/S1043661819305389
  53. Panahi Y, Ostadmohammadi V, Raygan F, Sharif MR, Sahebkar A. The effects of N-acetylcysteine administration on metabolic status and serum adiponectin levels in patients with metabolic syndrome: A randomized, double-blind, placebo-controlled trial. Journal of Functional Foods [Internet]. 2022 Dec 1;99:105299. Available from: https://www.sciencedirect.com/science/article/pii/S1756464622003693
  54. Rani M, Aggarwal R, Vohra K. Effect of N-Acetylcysteine on Metabolic Profile in Metabolic Syndrome Patients. Metabolic Syndrome and Related Disorders. 2020 Jun 17;
  55. Haber CA, Lam TKT, Yu Z, Gupta N, Goh T, Bogdanovic E, et al. Nacetylcysteine and taurine prevent hyperglycemia-induced insulin resistance in vivo: possible role of oxidative stress. American Journal of Physiology-Endocrinology and Metabolism. 2003 Oct;285(4):E744–53.
  56. Raffaele M, Barbagallo I, Licari M, Carota G, Sferrazzo G, Spampinato M, et al. N‐Acetylcysteine (NAC) Ameliorates Lipid‐Related Metabolic Dysfunction in Bone Marrow Stromal Cells‐Derived Adipocytes. Martel F, editor. Evidence-Based Complementary and Alternative Medicine [Internet]. 2018 Jan [cited 2025 Apr 28];2018(1). Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC6207898/
  57. Liu J, H. Irene Su, Jin X, Wang L, Huang J. The effects of N-acetylcysteine supplement on metabolic parameters in women with polycystic ovary syndrome: a systematic review and meta-analysis. Frontiers in Nutrition. 2023 Sep 29;10.
  58. Li B, Ming H, Qin S, Nice EC, Dong J, Du Z, et al. Redox regulation: mechanisms, biology and therapeutic targets in diseases. Signal Transduction and Targeted Therapy [Internet]. 2025 Mar 7;10(1). Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC11885647/
  59. Dludla PV, Mazibuko-Mbeje SE, Nyambuya TM, Mxinwa V, Tiano L, Marcheggiani F, et al. The beneficial effects of N-acetyl cysteine (NAC) against obesity associated complications: A systematic review of pre-clinical studies. Pharmacological Research [Internet]. 2019 Aug 1;146:104332. Available from: https://www.sciencedirect.com/science/article/abs/pii/S1043661819305389
  60. Jeremias A, Geetha Soodini, Gelfand E, Xu Y, Stanton RC, Horton ES, et al. Effects of N-Acetyl-Cysteine on Endothelial Function and Inflammation in Patients with Type 2 Diabetes Mellitus. Heart International. 2009 Jan 1;4(1):hi.2009.e7–7.
  61. Marasinghe CK, Indyaswan Tegar Suryaningtyas, Jung WK, Je JY. Protective Effect of NAcetylcysteine (NAC) on oxLDL-Induced Endothelial Dysfunction. Journal of Microbiology and Biotechnology. 2025 Aug 5;35:e2504039–9.
  62. Chennupati R, Solga I, Wischmann P, Dahlmann P, Celik FG, Pacht D, et al. Chronic anemia is associated with systemic endothelial dysfunction. Frontiers in Cardiovascular Medicine [Internet]. 2023 [cited 2024 Mar 14];10. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10205985/
  63. Peoples JN, Saraf A, Ghazal N, Pham TT, Kwong JQ. Mitochondrial dysfunction and oxidative stress in heart disease. Experimental & Molecular Medicine. 2019 Dec;51(12).
  64. N-acetylcysteine (NAC): from Clinical to Anti-Aging – Mitochon [Internet]. Mitochon. 2023 [cited 2025 Dec 4]. Available from: https://www.mitochon.it/en/n-acetylcysteine-nac-from-clinical-to-anti-aging/?v=b80bb7740288
  65. Zhou J, Terluk MR, Orchard PJ, Cloyd JC, Kartha RV. N-Acetylcysteine Reverses the Mitochondrial Dysfunction Induced by Very Long-Chain Fatty Acids in Murine Oligodendrocyte Model of Adrenoleukodystrophy. Biomedicines [Internet]. 2021 Dec 3 [cited 2022 Dec 6];9(12):1826. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8698433/
  66. Faghfouri AH, Zarezadeh M, Tavakoli-Rouzbehani OM, Radkhah N, Faghfuri E, Kord-Varkaneh H, et al. The effects of N-acetylcysteine on inflammatory and oxidative stress biomarkers: A systematic review and meta-analysis of controlled clinical trials. European Journal of Pharmacology [Internet]. 2020 Oct 5 [cited 2022 Aug 1];884:173368. Available from: https://pubmed.ncbi.nlm.nih.gov/32726657/
  67. Devrim-Lanpir A, Hill L, Knechtle B. How N-Acetylcysteine Supplementation Affects Redox Regulation, Especially at Mitohormesis and Sarcohormesis Level: Current Perspective. Antioxidants. 2021 Jan 21;10(2):153.
  68. Zhou J, Terluk MR, Orchard PJ, Cloyd JC, Kartha RV. N-Acetylcysteine Reverses the Mitochondrial Dysfunction Induced by Very Long-Chain Fatty Acids in Murine Oligodendrocyte Model of Adrenoleukodystrophy. Biomedicines [Internet]. 2021 Dec 3;9(12):1826. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8698433/
  69. Risk assessment of food supplements containing N-acetylcysteine (NAC) [Internet]. Available from: https://www.rivm.nl/bibliotheek/rapporten/2024-0086.pdf
  70. Teder K, Maddison L, Soeorg H, Meos A, Karjagin J. The Pharmacokinetic Profile and Bioavailability of Enteral N-Acetylcysteine in Intensive Care Unit. Medicina [Internet]. 2021 Nov 8 [cited 2022 Oct 30];57(11):1218. Available from: https://doi.org/10.3390%2Fmedicina57111218
  71. Greene SC, Noonan PK, Sanabria C, Peacock WF. Effervescent N-Acetylcysteine Tablets versus Oral Solution N-Acetylcysteine in Fasting Healthy Adults: An Open-Label, Randomized, Single-Dose, Crossover, Relative Bioavailability Study. Current Therapeutic Research. 2016;83:1–7.
  72. gov. 2025 [cited 2025 Dec 4]. Available from: https://clinicaltrials.gov/study/NCT06252519
  73. Rodella U, Honisch C, Gatto C, Paolo Ruzza, Jana D’Amato Tóthová. Antioxidant Nutraceutical Strategies in the Prevention of Oxidative Stress Related Eye Diseases. Nutrients. 2023 May 12;15(10):2283–3.
  74. Jambor B. Antioxidant Synergy: How Vitamin C, Selenium, and Glutathione Supercharge Your Health | OrganiClinic [Internet]. OrganiClinic. 2025 [cited 2025 Dec 4]. Available from: https://organiclinic.com/antioxidant-synergy-vitamin-c-selenium-glutathione/
  75. GlyNAC supplementation reverses aging hallmarks in aging humans [Internet]. Baylor College of Medicine. 2022. Available from: https://www.bcm.edu/news/glynac-supplementation-reverses-aging-hallmarks-in-aging-humans
  76. Kumar P, Liu C, Hsu JW, Chacko S, Minard C, Jahoor F, et al. Glycine and N‐acetylcysteine (GlyNAC) supplementation in older adults improves glutathione deficiency, oxidative stress, mitochondrial dysfunction, inflammation, insulin resistance, endothelial dysfunction, genotoxicity, muscle strength, and cognition: Results of a pilot clinical trial. Clinical and Translational Medicine. 2021 Mar;11(3).
  77. Team MA. The Best Liver Support Supplements [Internet]. Allergy Research Group. 2025 [cited 2025 Dec 4]. Available from: https://allergyresearchgroup.com/blogs/nutrition-in-focus/best-liver-support-supplements
  78. Manouchehr Khoshbaten, Akbar Aliasgarzadeh, Koorosh Masnadi, Tarzamani MK, Farhang S, Hosain Babaei, et al. N-Acetylcysteine Improves Liver Function in Patients with Non-Alcoholic Fatty Liver Disease. Hepatitis Monthly [Internet]. 2010 Mar;10(1):12. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC3270338/
  79. Ershad M, Naji A, Vearrier D. N Acetylcysteine [Internet]. Nih.gov. StatPearls Publishing; 2019. Available from: https://www.ncbi.nlm.nih.gov/books/NBK537183/
  80. N-ACETYL CYSTEINE (NAC): Overview, uses, side effects, precautions, interactions, dosing and reviews [Internet]. www.webmd.com. Available from: https://www.webmd.com/vitamins/ai/ingredientmono-1018/n-acetyl-cysteine-nac
  81. Millea PJ. N-Acetylcysteine: Multiple Clinical Applications. American Family Physician [Internet]. 2009 Aug 1;80(3):265–9. Available from: https://www.aafp.org/pubs/afp/issues/2009/0801/p265.html
  82. Campbell CL, Berger PB, Nuttall GA, Orford JL, Santrach PJ, Oliver WC, et al. Can N-acetylcysteine reverse the antiplatelet effects of clopidogrel? An in vivo and vitro study. American Heart Journal. 2005 Oct;150(4):796–9.
  83. Niemi TT, Munsterhjelm E, Pöyhiä R, Hynninen MS, Salmenperä MT. The effect of N-acetylcysteine on blood coagulation and platelet function in patients undergoing open repair of abdominal aortic aneurysm. Blood Coagulation & Fibrinolysis: An International Journal in Haemostasis and Thrombosis [Internet]. 2006 Jan 1 [cited 2023 Feb 25];17(1):29–34. Available from: https://pubmed.ncbi.nlm.nih.gov/16607076/
  84. Eligini S, Porro B, Giancarlo Aldini, Colli S, Banfi C. N-Acetylcysteine Inhibits Platelet Function through the Regeneration of the Non-Oxidative Form of Albumin. Antioxidants [Internet]. 2022 Feb 23 [cited 2023 Dec 17];11(3):445–5. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8944739/
  85. Bresette CA, Ashworth KJ, Paola JD, Ku DN. N-Acetyl Cysteine Prevents Arterial Thrombosis in a Dose-Dependent Manner In Vitro and in Mice. Arteriosclerosis Thrombosis and Vascular Biology. 2023 Dec 21;44(2).
  86. Margaritelis NV. Personalized redox biology: Designs and concepts. Free Radical Biology and Medicine. 2023 Nov;208:112–25.
  87. Kazakov Y, Halperin A, Brainina K. Artificial intelligence as a potential tool for oxidative stress estimation in medicine. Exploration of Digital Health Technologies. 2025 Jul 15;3.
  88. Devrim-Lanpir A, Hill L, Knechtle B. How N-Acetylcysteine Supplementation Affects Redox Regulation, Especially at Mitohormesis and Sarcohormesis Level: Current Perspective. Antioxidants. 2021 Jan 21;10(2):153.
  89. Haines DD, Rose SC, Cowan FM, Mahmoud FF, Rizvanov AA, Arpad Tosaki. Leveraging Artificial Intelligence and Modulation of Oxidative Stressors to Enhance Healthspan and Radical Longevity. Biomolecules. 2025 Oct 24;15(11):1501–1.
  90. Sahasrabudhe SA, Terluk MR, Kartha RV. N-acetylcysteine Pharmacology and Applications in Rare Diseases—Repurposing an Old Antioxidant. Antioxidants [Internet]. 2023 Jun 21;12(7):1316–6. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10376274/
  91. Bhatia A, Maddox TM. Remote Patient Monitoring in Heart Failure: Factors for Clinical Efficacy. International Journal of Heart Failure. 2021;3(1):31.