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Nattokinase: Natto’s Secret Weapon Against Heart Clots and Plaques

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Introduction

Cardiovascular disease remains the leading cause of morbidity and mortality worldwide, and existing preventive strategies, while effective, leave substantial residual risk at both the population and individual level. This gap has driven growing interest in food-derived bioactive compounds that may favorably modulate thrombosis, lipid metabolism, vascular function, and low-grade inflammation across the lifespan. Within this landscape, nattokinase has emerged as candidate interface between traditional dietary practices and modern cardiovascular prevention.

Nattokinase is a serine protease produced by Bacillus subtilis during the fermentation of soybeans to create nattō, a staple of the traditional Japanese diet that has been consumed for centuries. Epidemiological data from large Japanese cohorts and cerebrovascular mortality, independent of total soy intake, raising the possibility that specific fermentation-derived components, particularly nattokinase, confer unique vascular benefits. Beyond observational signals, nattokinase has demonstrated fibrinolytic, antithrombotic, antihypertensive, anti-atherosclerotic, and lipid-modifying actions in preclinical models and early clinical studies, including reductions of blood pressure, improvements in lipid profiles, and regression of carotid intima media thickness and plaque area in selected cohorts.

At the same time, the clinical evidence base is heterogenous, with variability in dosing, formulations, study populations, and endpoints, and an absence of large, long-term outcome trials comparable to those for statins or antithrombotic drugs. Safety considerations, including bleeding risk, interactions with anticoagulant or antiplatelet therapy, and quality control issues in the supplement market, further underscore the need for a structured, evidence-based appraisal before broad incorporation into preventive cardiometabolic care. This article therefore examines nattokinase at the crossroads of traditional nutrition and contemporary cardiovascular prevention, integrating epidemiological, mechanistic, and clinical data to clarify its potential role and current limitations as an adjunct in the management of vascular and metabolic risk.

From Nattō to Nattokinase: Traditional Japanese Fermentation and the Discovery of a Fibrinolytic Enzyme

Natto, a traditional Japanese food characterized by its sticky texture, pungent aroma, and unique flavor, has been consumed for over a thousand ears for its purported cardiovascular benefits. Produced through the fermentation of boiled soybeans by the bacterium Bacillus subtilis var. natto, this dietary staple was historically nicknamed “vegetable cheese” for its high protein content and enzymatic complexity. While anedoctal evidence linking natto consumption to vascular health persisted for centuries, the specific bioactive agent responsible for these effects remained unidentified until the late 20th century [1,2,3,4].

The definitive discovery of nattokinase ccurred in 1980 at the University of Chicago Medical School, where researcher Hiroyuki Sumi was screening natural agents for thrombolytic potential. In a pivotal experiment popularly cited in the literature, Sumi applied extract from 173 different foods to artificial thrombi (fibrin plates) at 37oC (body temperature). He observed that the extract from natto induced potent fibrinolysis, completely dissolving the thrombus within 18 hours, a rate significantly exceeding that of endogenous plasmin. Sumi subsequently isolated the enzyme responsible for this activity and named it “nattokinase”, designating it as a novel fibrinolytic protease derived from the fermentation process rather than the soy substrate itself [1,5].

Biochemically, natokinase (NK) is a 275-amino acid single-chain polypeptide with a molecular weight of approximately 27.7 kDa and an isoelectric point (pI) of roughly 8.6-8.7. Despite its name, nattokinase is not a kinase enzyme; rather it belongs to the substilisin family of alkaline serine proteases (specifically homologous to substilin E and BPN). Its catalytic mechanism relies on a conserved catalytic triad which are aspartate (Asp32), histidine (His64), and serine (Ser221) which facilitates the cleavage of cross-linked fibrin. Importantly, nattokinase lacks disulfide bonds, contributing to its relative instability under acidic conditions (pH <5.0) while maintaining robust activity at neutral to alkaline pH ranges (pH 6.0-12.0), a characteristic that dictates the necessity for enteric coating or specific delivery technologies in oral supplementation to ensure survival through gastric acid [6,7,8,9].

Habitual Nattō Intake and Cardiovascular Mortality: Population Data Hinting at Food-Specific Benefits Beyond Soy Protein

While randomized trials of nattokinase are a relatively recent development, large-scale epidemiological data from Japan provide a compelling historical signal for the cardiovascular benefits of its source food, natto. The Takayama Study, a population-based cohort involving nearly 29,000 adults, offers perhaps the most specific evidence to date. Over 16 years of follow-up, researchers observed that participants in the highest quartile of natto intake had a significantly lower risk of mortality from total cardiovascular disease (Hazard Ratio [HR]=0.75; 95% CI:0.64-0.88) and ischemic stroke (HR=0.67, 95%CI: 0.47-0.95) compared to those in the lowest quartile. Crucially this protective association was not observed for total soy protein or other non-fermented soy foods (such as tofu), suggesting that the benefit was driven by factors specific to the fermentation process, most plausibly the fibrinolytic enzyme nattokinase rather than generic soy isoflavones [10].

These findings were further corroborated by the Japan Public Health Center-based (JPHC) Prospective Study, which followed nearly 93,000 participants for approximately 15 years. This analysis similarly reported an inverse association between the intake of fermented soy products and cardiovascular mortality, with natto consumption specifically linked to a reduced risk of death from cardiovascular causes in both men and women. The consistency of these signals across major cohorts reinforces the hypothesis that natto is not merely a marker of a healthy “traditional diet” but a source of unique bioactive compounds. By isolating the benefit to fermented soy, these studies help bridge the gap between anedoctal longevity claims and a biologically plausible mechanism, pointing directly toward the anti-thrombotic and circulatory potential of nattokinase [11].

Clinical Evidence for Atherosclerosis and Lipids

High-Dose Nattokinase and Carotid Atherosclerosis: Insights from a 1,062- Participant Open-Label Study

While early trials primarily investigated nattokinase for its fibrinolytic properties at standard doses (typically 2,000-4,000 FU/day), more recent clinical efforts have examined its potential for structural vascular remodeling at significantly higher intakes. The most substantial evidence in this domain comes from a 2022 study by Chen et al., which followed 1,062 participants with hyperlipidemia and mild atherosclerosis over a 12-month period. In this open-label investigation, participants receiving a high daily dose of 10,800 FU demonstrated a remarkable regression in carotid artery pathology. Specifically, the treatment group exhibited a 36.6% reduction in carotid plaque surface area (CPS) and a 21.7% decrease in common carotid artery intima media thickness (CCA-IMT), changes that were statistically significant compared to baseline changes in these structural markers, suggesting a dose-dependent threshold for anti-atherosclerotic efficacy [12,13,14].

Effects on Lipid Parameter and Carotid Structure: Triglycerides, LDL-C, HDL-C, and Plaque Burden

Beyond structural regression, high-dose nattokinase administration was associated with comprehensive improvements in the lipid profile, reinforcing its potential as a metabolic modulator. The 10,800 FU/day regimen led to significant reductions in total cholesterol, LDL-cholesterol, and triglycerides, alongside a concurrent elevation in HDL-cholesterol. The magnitude of these shifts was clinically meaningful, with improvement rates in lipid parameters ranging from approximately 66% to 95% of participants. Interestingly, the study observed that the lipid-lowering effects were more pronounced in participants with higher-baseline metabolic risk factors, such as those who smoked, consumed alcohol, or had an elevated BMI. These findings imply that nattokinase may exert a multifaceted cardioprotective effect, simultaneously targeting the “soft” metabolic drivers of dyslipidemia and the “hard” structural burden of established plaque, though the open label design and lack of placebo control group necessitate confirmation in rigorous randomized controlled trials [12,13].

Randomized trials and Cardiometabolic Risk

Nattokinase in Randomized Controlled Trials: Blood Pressure, Coagulation Markers, and Composite Cardiometabolic Outcomes

Beyond open-label observation, rigorous randomized controlled trials (RCTs) have sought to isolate the physiological effects of nattokinase on hemodynamic coagulation parameters. In a pivotal double-blind, placebo-controlled trial involving 85 participants with pre-hypertension or stage 1 hypertension, Kim et al. (2008) demonstrated that supplementation with 2,000FU/day for eight weeks significantly reduced both systolic (-5.55mmHg) and diastolic (2.84 mmHg) blood pressure compared to placebo. These findings were reinforced by Jensen et al. (2016) in a North American cohort, where nattokinase administration was associated with beneficial changes in blood pressure and a notable reduction in von Wilebrand factor (vWF), an endothelial activation. Marker, particularly in female subpopulations [15,16].

Further investigating its haemostatic influence, Hsia et al. (2009) conducted a trial involving healthy volunteers, patients with cardiovascular risk factors, and dialysis patients. Their results indicated that a daily regimen of 4,000 FU significantly decreased plasma levels of fibrinogen (by 7-10%), factor VII, and factor VIII after two months, suggesting a broad antithrombotic potential that extends across different risk profiles. More recently, a 2024 trial explored the impact of nattokinase on subclinical atherosclerosis progression. While it did not show a reversal of carotid plaque at standard doses in healthy low-risk individuals, it highlighted the necessity of dose optimization and patient selection in future cardiometabolic outcome studies [17,18,19].

Combination Strategies with Red Yeast rice and Standard therapies in Stable Cardiovascular Disease

Recognizing that cardiovascular risk is multifactorial, researchers have evaluated nattokinase as part of synergistic combination therapies, most notably with Red Yeast Rice (RYR), a natural source monacolin K (lovastatin). In a randomized parallel comparison study by Yang et al. (2009), a combined formulation of nattokinase and RYR was superior to nattokinase alone in altering the profile of hyperlipidemic patients. The combination therapy yielded significant reductions in total cholesterol, LDL-cholesterol (up to 25%), and the total cholesterol/HDL-C ratio, whereas nattokinase monotherapy at the tested dose (standard 2,000 FU range) did not produce statistically significant lipid-lowering effects in this specific cohort [20].

This synergy suggests a “dual-hit” strategy: RYR targets hepatic cholesterol synthesis, while nattokinase addresses the hemorheological and fibrinolytic aspects of vascular health. Emerging data also point to the potential of adding this combination to standard statin therapy in patients with stable cardiovascular disease to manage residual lipid risk and inflammatory indices, offering a complementary approach for patients who may not achieve targets with statin monotherapy alone or who seek nutraceutical adjuncts to lower effective pharmaceutical doses [21].

Mechanism of Action

Fibrinolytic and Antithrombotic Actions: Plasminogen Activation, Clot Degradation, and Platelet-Modulating Effects

Nattokinase (NK) exerts its fibrinolytic effects through a sophisticated dual mechanism that distinguishes it from many other antithrombotic agents. Its primary action involves the direct proteolysis of cross-linked fibrin, dissolving thrombi through a mechanism largely independent of endogenous fibrinolytic factors. However, its potency is significantly amplified by a secondary, indirect pathway: NK catalyzes the conversion of plasminogen to plasmin and facilitates the conversion of prourokinase to urokinase (u-PA), thereby enhancing the body’s intrinsic thrombolytic capacity. Crucially, NK also targets the regulatory “brakes” of the fibrinolytic system by cleaving and inactivating Plaminogen Activator Inhibitor-1 (PAI-1). Since elevated PAI-1 is a key driver of hypofibrinolysis in metabolic syndrome and obesity, this specific inhibition restores the natural activity of tissue plasminogen activator (t-PA), effectively promoting clot lysis in thrombogenic environments [4,5,22,23].

Beyond fibrinolysis, nattokinase demonstrates significant antiplatelet activity, offering a complementary defense against arterial thrombosis. In vitro and in vivo models indicate that NK inhibits platelet aggregation induced by collagen and thombin, an effect mediated by the blockade of thromboxane A2 (TXA2) formation, a mechanism analogous to, though pharmacologically distinct from, aspirin. This dual action allows NK to not only dissolve existing fibrin clots but also impede the initial platelet activation and recruitment steps that precipitate arterial occlusion following vascular injury, all while maintaining a safety profile that suggests a lower bleeding risk compared to conventional antiplatelet drugs [4,24,25].

Anti-Atherosclerotic, Lipid-Modulating, and Antihypertensive Mechanisms: Vascular Biology Beyond Fibrinolysis

The cardiovascular benefits of nattokinase extend into vascular biology and metabolic regulation, addressing the root causes of atherosclerosis. At the molecular level, NK has been shown to attenuate endothelial inflammation, a critical early step in plaque formation. It achieves this by inhibiting the Nuclear Factor-kappa B (NF-kB) signaling pathway and reducing the expression of pro-inflammatory adhesion molecules like CVAM-1 and ICAM-1, which are essential for monocyte recruitment to the arterial wall. Furthermore, NK exerts a potent antioxidant effect that inhibits the oxidation of Low-Density Lipoprotein (LDL), a pivotal event in the transformation of macrophages into foam cells within nascent atheroma [4,12,23,26].

Metabolically, NK appears to function as a pleiotropic lipid-lowering agent. Mechanistic studies suggest it inhibits hepatic HMG-CoA reductase (the rate-limiting enzyme in cholesterol synthesis) and enhances the activity of lipoprotein lipase (LPL) and hormone-sensitive lipase (HSL), thereby facilitating the clearance of triglyceride-rich lipoproteins and promoting reverse cholesterol transport. Concurrently, its antihypertensive properties are linked to the inhibition of Angiotensin Converting Enzyme (ACE), effectively dampening the renin-angiotensin-aldosterone system (RAAS) to lower systemic vascular resistance. By integrating lipid modulation, anti-inflammatory signaling, and blood pressure control, nattokinase addresses the multifaceted pathophysiology of vascular aging and metabolic disease [4,26,27,28].

Dosing, Formulations, and Pharmacokinetics

Functional units, Dose-Response, and the Emerging Concept of a Therapeutic Threshold for Nattokinase

Nattokinase potency is standardized in Fibrinolytic Units (FU), a measure of its activity to degrade fibrin, rather than by mass (miligrams). Historically, the “standard” maintenance dose has been established at 2,000 FU per day, roughly equivalent to the nattokinase content in one commercial pack (approx.. 50g) of fresh natto. This dosage has shown efficacy in modulating blood pressure and clotting factors in early trials. However, recent clinical investigations suggest a crucial dose-dependent threshold for structural vascular benefits. The divergent outcomes between studies using 2,000-4,000 FU and those employing higher doses (e.g., 10,800 FU) imply that while standard doses may suffice for hemostatic maintenance, significantly higher enzymatic activity may be required to drive plaque regression and lipid modification this shifting paradigm points toward a “therapeutic threshold”, a minimum level of circulating activity necessary to overcome the homeostatic inertia of established atherosclerosis [4,14,28,29,30].

Oral Bioavailability, Enzyme Stability, Variability Across Commercial Preparations

As a protein, nattokinase faces the pharmacokinetic challenge of surviving gastric acid (pH 1.2-2.0) and intestinal proteolysis to reach the systemic circulation intact. Although nattokinase is relatively stable at neutral pH, it is rapidly inactivated in highly acidic environments, necessitating the use of enteric-coated technologies or acid-resistant capsules in high-quality formulations to prevent denaturation in the stomach. Pharmacokinetic studies in humans indicate that following oral administration, nattokinase or its active peptide fragments can be detected in serum, with peak concentrations occurring approximately 13 hours post-ingestion, suggesting a prolonged biological half0life that supports once-daily dosing. However, the market is characterized by significant heterogeneity; commercial preparations vary widely in their actual fibrinolytic activity, purity, and stability, with some products failing to meet label claims, this variability underscores the importance of sourcing from manufacturers that provide third-party validation of enzymatic activity (FU) and utilize delivery systems proven to ensure bioavailability [4,14,25,29,31,32,34].

Safety, Adverse Effects, and Drug Interactions

Bleeding Risk, Perioperative Considerations, and Interactions with antithrombotic Medications

Nattokinase (NK) possesses potent fibrinolytic and antiplatelet properties, which, while beneficial for thrombosis prevention, necessitate caution in specific clinical contexts. Although safety data from human trials generally report no severe adverse events at standard doses (up to 4,000 FU/day) in healthy individuals, case reports have documented serious hemorrhagic episodes when NK is combined with other antithrombotic agents. Notably, a case of acute cerebella hemorrhage occurred in a patient taking NK (400mg daily) concurrently with aspirin, likely due to a synergistic inhibition of hemostasis in the presence of underlying cerebral microangiopathy. Consequently, authoritative guidelines and clinical reviews strongly advice against the concomitant use of nattokinase with antiplatelet drugs (e.g., aspirin, clopidogrel) or anticoagulants (e.g., warfarin, DOACs) unless under strict medical supervision, as the additive effect may precipitate spontaneous bleeding [4,35,36,37].

Perioperative management guidelines further reflect this risk profile. Given its fibrinolytic half-life and mechanism, it is recommended to discontinue nattokinase at least 1–2 weeks prior to intermediate- or high-risk surgical procedures to normalize hemostatic function. Re-initiation should be delayed until postoperative hemostasis is fully secured, mirroring protocols for other nutraceuticals with anticoagulant potential like fish oil or garlic [38].

Regulatory status, Product Quality, and Gaps in Long-Term Safety Surveillance

Nattokinase occupies a complex regulatory niche, classified as a dietary supplement in the United States with self-affirmed Generally Recognized as Safe (GRAS) status for specific formulations like NSK-SD®. In Europe, it holds “Novel Food” authorization from the European Food Safety Authority (EFSA), contingent upon strict safety criteria such as the removal of Vitamin K2 to prevent anticoagulant interference. However, clinical consistency is frequently compromised by significant heterogeneity in commercial preparations. While potency is standardized in Fibrinolytic Units (FU), independent analyses reveal widespread discrepancies in enzymatic activity and purity between manufacturers. High-quality formulations employ patented processes to ensure stability and the complete removal of Vitamin K2 (<1 ppm), whereas generic products often fail to meet label claims, necessitating the use of third-party verified supplements to ensure reproducible therapeutic outcomes [39,40,41].

Despite a favourable safety profile in animal toxicology and short-term human trials, data regarding chronic, multi-year consumption remain sparse. Most clinical studies extend no longer than six months, leaving potential cumulative immunogenicity or long-term hemostatic effects in vulnerable populations uncharacterized. The absence of centralized pharmacovigilance for dietary supplements further obscures rare adverse events, highlighting an urgent need for longitudinal registry studies to validate its safety for lifelong preventive use [42,43].

Nattokinase within Preventive Cardio-Metabolic Care

Rationale and Positioning in Prevention Strategies

The integration of nattokinase into preventive cardiometabolic care is increasingly supported by its multifaceted mechanism of action, which addresses several pillars of residual cardiovascular risk: thrombosis, hypertension, and dyslipidemia. In the landscape of primary prevention, where the goal is to mitigate risk factors before the onset of overt clinical disease, nattokinase offers a unique “bioactive bridge” between dietary modification and pharmacological intervention. Unlike traditional antiplatelet agents (e.g., aspirin), which are no longer routinely recommended for primary prevention in low-to-moderate risk adults due to bleeding liabilities, nattokinase provides a milder, regulatory effect on hemostasis. It enhances endogenous fibrinolysis by upregulating tissue plasminogen activator (t-PA) and degrading cross-linked fibrin, without disrupting normal wound healing mechanisms to the same extent as pharmaceutical anticoagulants. This profile positions it as a viable option for patients seeking nutraceutical support for vascular health, particularly those with subclinical atherosclerosis or metabolic syndrome who are not yet candidates for aggressive pharmaceutical therapy [4,42,44].

Clinical Utility in Dyslipidemia and Hypertension

Within the context of metabolic management, nattokinase demonstrates significant utility as an adjunctive agent for optimizing lipid profiles and blood pressure. Clinical trials have indicated that high-dose supplementation (e.g., >4,000 FU/day) can effectively reduce low-density lipoprotein cholesterol (LDL-C) and triglycerides while simultaneously elevating high-density lipoprotein cholesterol (HDL-C), likely through the proteolytic cleavage of lipid-transporting proteins and the inhibition of LDL oxidation. Furthermore, its ability to inhibit Angiotensin Converting Enzyme (ACE) parallels the mechanism of first-line antihypertensive drugs, offering a dual benefit for patients with the “metabolic dyad” of hyperlipidemia and pre-hypertension. Recent evidence from a large-scale study involving 1,062 participants suggests that this dual action may translate into structural vascular benefits, specifically the regression of carotid intima-media thickness (CIMT) and the reduction of plaque burden, thereby targeting the anatomical substrate of future cardiovascular events [45,46].

Synergistic Approaches and Implementation

For comprehensive cardiometabolic care, nattokinase is rarely used in isolation but rather as part of a synergistic “polypill” strategy alongside other evidence-based nutraceuticals. The combination of nattokinase with red yeast rice (monacolin K) has shown superior efficacy in improving lipid parameters compared to either agent alone, offering a potent natural alternative for patients with statin intolerance. However, the clinical implementation of nattokinase requires strategic patient selection. It is most appropriate for individuals with elevated thrombotic risk (e.g., high fibrinogen levels), sedentary lifestyles, or those needing mild blood pressure support. Conversely, its use in secondary prevention, patients with established history of stroke or myocardial infarction, must be approached with caution and rigorous coordination with prescribing physicians to avoid potentially dangerous pharmacodynamic interactions with standard dual antiplatelet therapy or direct oral anticoagulants [47,48].

Future Directions and Research Priorities

Future work on nattokinase is converging on a few clear priorities that span basic science, clinical outcomes, and formulation science [4,50].

In the near term, the most critical need is for large, long-duration randomized controlled rials powered for hard outcomes such as myocardial infarction, stroke, and cardiovascular mortality rather than surrogate markers alone. Current trials are relatively small and short, and new multi-year studies are now being designed to test whether nattokinase can slow subclinical atherosclerosis, reduce arterial stiffness, and preserve cognition in older adults at cardiometabolic risk. Parallel RCTs are also underway to clarify its effects on inflammation lipid peroxidation, and comprehensive cardiometabolic risk scores in dyslipidemic populations [50,51,52].

On the mechanistic and translational side, research priorities include defining precise pharmacokinetics and bioavailability in humans, mapping dose-response relationships, and fully characterizing drug-nutrient interactions with antiplatelet and anticoagulant regimens. Advances in biotechnology are focusing on engineered strains and molecular modification of nattokinase to improve thermostability, catalytic efficiency, and yield, which could support pharmaceutical-grade preparations with tighter quality control. Finally, long-term safety surveillance systems and standardized manufacturing/ labeling standards are viewed as essential prerequisites before nattokinase can be more widely positioned as a routine component of preventive cardiometabolic care [4,28,36,49,53,54].

Conclusion

Nattokinase can be reasonably positioned as a promising but not yet definitive adjunct in preventive cardiometabolic care, bridging traditional natto consumption with modern strategies to reduce vascular risk. Across epidemiological, mechanistic, and clinical domains, the enzyme demonstrates biologically plausible and increasingly consistent effects on fibrinolysis, blood pressure, lipid profiles and surrogate markers of atherosclerosis, suggesting potential to address residual risk that persists despite lifestyle optimization and conventional pharmacotherapy. At the same time, the current evidence base is constrained by heterogenous formulations, variable dosing, short trial durations, and lack of large outcome studies powered for myocardial infarction, stroke, or cardiovascular mortality, limiting the strength of any causal interference.

From a safety and implementation standpoint, concerns about bleeding in combination with antithrombotic rugs, uncertainties around perioperative management, and uneven product quality in the supplement market argue against routine, unsupervised use, particularly in high-risk or polymedicated patients. Until standardized, vitamin-K-free preparations are more widely adopted and supported by long-term pharmacovigilance and robust randomized trials, nattokinase is best considered a targeted option for selected individuals within a comprehensive cardiometabolic prevention plan that prioritizes lifestyle intervention and guideline-directed medical therapy.

Reference

  1. Nattokinase [Internet]. Springboard4health.com. 2025 [cited 2025 Dec 22]. Available from: https://www.springboard4health.com/notebook/health_nattokinase.html
  2. Sumi H, Hamada H, Tsushima H, Mihara H, Muraki H. A novel fibrinolytic enzyme (nattokinase) in the vegetable cheese Natto; a typical and popular soybean food in the Japanese diet. Experientia. 1987 Oct;43(10):1110–1.
  3. Wang C, Chen J, Tian W, Han Y, Xu X, Ren T, et al. Natto: A medicinal and edible food with health function. Chinese Herbal Medicines [Internet]. 2023 Jul 1;15(3):349–59. Available from: https://www.sciencedirect.com/science/article/pii/S1674638423000564
  4. Chen H, McGowan EM, Ren N, Lal S, Nassif N, Shad-Kaneez F, et al. Nattokinase: A Promising Alternative in Prevention and Treatment of Cardiovascular Diseases. Biomarker Insights. 2018 Jan;13:117727191878513.
  5. Weng Y, Yao J, Sparks S, Wang KY. Nattokinase: An Oral Antithrombotic Agent for the Prevention of Cardiovascular Disease. International Journal of Molecular Sciences [Internet]. 2017 Feb 28;18(3). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372539/
  6. Lin HTV, Wu GJ, Hsieh MC, Chang SH, Tsai GJ. Purification and Characterization of Nattokinase from Cultural Filtrate of Red Alga Porphyra Dentata Fermented by Bacillus Subtilis N1. Journal of Marine Science and Technology [Internet]. 2015 Apr 1 [cited 2025 Sep 28];23(2):240–8. Available from: https://jmstt.ntou.edu.tw/journal/vol23/iss2/13/
  7. National Library of Medicine. National center for biotechnology information [Internet]. Nih.gov. National Library of Medicine; 2025. Available from: https://www.ncbi.nlm.nih.gov/
  8. Guangbo Y, Min S, Wei S, Lixin M, Chao Z, Yaping W, et al. Heterologous expression of nattokinase from B. subtilis natto using Pichia pastoris GS115 and assessment of its thrombolytic activity. BMC Biotechnology. 2021 Aug 9;21(1).
  9. Jamali N, Vahedi F, Soltani Fard E, Taheri-Anganeh M, Taghvimi S, Khatami SH, et al. Nattokinase: Structure, applications and sources. Biocatalysis and Agricultural Biotechnology. 2023 Jan;47:102564.
  10. Nagata C, Wada K, Tamura T, Konishi K, Goto Y, Koda S, et al. Dietary soy and natto intake and cardiovascular disease mortality in Japanese adults: the Takayama study. The American Journal of Clinical Nutrition. 2016 Dec 7;105(2):426–31.
  11. Katagiri R, Sawada N, Goto A, Yamaji T, Iwasaki M, Noda M, et al. Association of soy and fermented soy product intake with total and cause specific mortality: prospective cohort study. BMJ. 2020 Jan 29;m34.
  12. Chen H, Chen J, Zhang F, Li Y, Wang R, Zheng Q, et al. Effective management of atherosclerosis progress and hyperlipidemia with nattokinase: A clinical study with 1,062 participants. Frontiers in Cardiovascular Medicine [Internet]. 2022;9:964977. Available from: https://pubmed.ncbi.nlm.nih.gov/36072877/
  13. com. New Study Reveals: High-Dose Supplement Shrinks Arterial Plaque by 36% [Internet]. Nad.com. 2025. Available from: https://www.nad.com/news/new-study-reveals-high-dose-supplement-shrinks-arterial-plaque-by-36
  14. Gerti Tashko, MD. What Is Nattokinase? Nattokinase comes from natto, a traditional Japanese food made from fermented soybeans. This enzyme helps the body dissolve fibrin, a protein involved in clot formation. [Internet]. Linkedin.com. 2025 [cited 2025 Dec 22]. Available from: https://www.linkedin.com/pulse/higher-dose-nattokinase-plaque-cholesterol-gerti-tashko-md-bh4we
  15. Kim JY, Gum SN, Paik JK, Lim HH, Kim K, Ogasawara K, et al. Effects of Nattokinase on Blood Pressure: A Randomized, Controlled Trial. Hypertension Research [Internet]. 2008 Aug 1;31(8):1583–8. Available from: https://www.nature.com/articles/hr2008203
  16. Jensen G, Lenninger M, Ero MP, Benson K. Consumption of nattokinase is associated with reduced blood pressure and von Willebrand factor, a cardiovascular risk marker: results from a randomized, double-blind, placebo-controlled, multicenter North American clinical trial. Integrated Blood Pressure Control. 2016 Oct;Volume 9:95–104.
  17. Hsia CH, Shen MC, Lin JS, Wen YK, Hwang KL, Cham TM, et al. Nattokinase decreases plasma levels of fibrinogen, factor VII, and factor VIII in human subjects. Nutrition Research [Internet]. 2009 Mar 1 [cited 2023 Jan 21];29(3):190–6. Available from: https://www.sciencedirect.com/science/article/abs/pii/S0271531709000220?via%3Dihub
  18. Chen H, McGowan EM, Ren N, Lal S, Nassif N, Shad-Kaneez F, et al. Nattokinase: A Promising Alternative in Prevention and Treatment of Cardiovascular Diseases. Biomarker Insights. 2018 Jan;13:117727191878513.
  19. Hodis HN, Mack WJ, Meiselman HJ, Kalra V, Liebman H, Hwang-Levine J, et al. Nattokinase atherothrombotic prevention study: A randomized controlled trial. Clinical Hemorheology and Microcirculation [Internet]. 2021 [cited 2023 May 29];78(4):339–53. Available from: https://pubmed.ncbi.nlm.nih.gov/33843667/
  20. Yang NC, Chou Bs CW, Chen CY, Hwang KL, Bs Y. Combined nattokinase with red yeast rice but not nattokinase alone has potent effects on blood lipids in human subjects with hyperlipidemia. Asia Pac J Clin Nutr [Internet]. 2009 [cited 2025 Dec 22];18(3):310–7. Available from: https://apjcn.qdu.edu.cn/18_3_12.pdf
  21. Chen S, Liu F, Li J, Liang F, Li J, Cao J, et al. Evaluation of NaTto Red Yeast Rice on Regulating Blood Lipid (ENTRY) Study: A Multicenter, Double‐Placebo, Double‐Blinded, Randomized Controlled Trial in Chinese Adults. Chronic Diseases and Translational Medicine. 2025 Apr 24;11(2):122–9.
  22. Ashraf H, Meer B, Naz R, Saeed A, Anwar P. Fibrinolytic Enzyme: Restoration Tool for Obliteration of Blood Clots. Journal of Molecular Imaging & Dynamics. 2017;7(2).
  23. Naoki Ohkura, Riyo Morimoto-Kamata. Antithrombotic Natural Products That Inhibit Plasminogen Activator Inhibitor 1 (PAI-1). BPB Reports. 2024 Jan 1;7(2):51–5.
  24. Jang JY, Kim TS, Cai J, Kim J, Kim Y, Shin K, et al. Nattokinase improves blood flow by inhibiting platelet aggregation and thrombus formation. Laboratory Animal Research. 2013 Jan 1;29(4):221–1.
  25. What Is Nattokinase? Mechanism, Bioavailability, and How It Works [Internet]. BlueRipple Health. 2025 [cited 2025 Dec 22]. Available from: https://blueripple.com/natto/natto-fundamentals/
  26. Chiu HW, Chou CL, Lee KT, Shih CC, Huang TH, Sung LC. Nattokinase attenuates endothelial inflammation through the activation of SRF and THBS1. International Journal of Biological Macromolecules [Internet]. 2024 Apr 27;268:131779. Available from: https://www.sciencedirect.com/science/article/abs/pii/S0141813024025844
  27. Murakami K, Yamanaka N, Ohnishi K, Fukayama M, Yoshino M. Inhibition of angiotensin I converting enzyme by subtilisin NAT (nattokinase) in natto, a Japanese traditional fermented food. Food & Function. 2012;3(6):674.
  28. Wei C, Cai R, Song Y, Liu X, Xu HL. Research Progress of Nattokinase in Reducing Blood Lipid. Nutrients. 2025 May 24;17(11):1784.
  29. Ero MP, Ng CM, Mihailovski T, Harvey NR, Lewis BH. A pilot study on the serum pharmacokinetics of nattokinase in humans following a single, oral, daily dose. Alternative therapies in health and medicine [Internet]. 2013;19(3):16–9. Available from: https://pubmed.ncbi.nlm.nih.gov/23709455/
  30. Kurosawa Y, Nirengi S, Homma T, Esaki K, Ohta M, Clark JF, et al. A single-dose of oral nattokinase potentiates thrombolysis and anti-coagulation profiles. Scientific Reports [Internet]. 2015 Jun 25;5(1):11601. Available from: https://www.nature.com/articles/srep11601
  31. Zhou X, Liu L, Zeng X. Research progress on the utilisation of embedding technology and suitable delivery systems for improving the bioavailability of nattokinase: A review. Food Structure. 2021 Oct;30:100219.
  32. Pravin Rewale. Nattokinase Market Demand & Forecast to 20332 [Internet]. Persistence Market Research. 2025 [cited 2025 Dec 22]. Available from: https://www.persistencemarketresearch.com/market-research/nattokinase-market.asp
  33. Habashy R, Khoder M, Isreb A, Alhnan MA. A Novel Multilayer Natural Coating for Fed-State Gastric Protection. Pharmaceutics. 2022 Jan 26;14(2):283.
  34. Law D, Zhang Z. Stabilization and Target Delivery of Nattokinase Using Compression Coating. Drug Development and Industrial Pharmacy [Internet]. 2007 Jan [cited 2025 Dec 22];33(5):495–503. Available from: https://magistralbr.caldic.com/storage/product-files/661303119.pdf
  35. Chang YY, Liu JS, Lai SL, Wu HS, Lan MY. Cerebellar Hemorrhage Provoked by Combined Use of Nattokinase and Aspirin in a Patient with Cerebral Microbleeds. Internal Medicine [Internet]. 2008;47(5):467–9. Available from: https://www.jstage.jst.go.jp/article/internalmedicine/47/5/47_5_467/_article
  36. Nattokinase | Memorial Sloan Kettering Cancer Center [Internet]. www.mskcc.org. Available from: https://www.mskcc.org/cancer-care/integrative-medicine/herbs/nattokinase
  37. What is nattokinase and its use in preventing or treating conditions associated with blood clotting? [Internet]. Droracle.ai. 2025 [cited 2025 Dec 22]. Available from: https://www.droracle.ai/articles/531222/what-is-nattokinase-and-its-use-in-preventing-or
  38. Drug Discontinuation Before Surgery – Guidelines and Recommendations [Internet]. The Anesthesia Guide. 2025. Available from: https://anesthguide.com/topic/discontinuation-times-of-medications-before-surgery/
  39. ‌S. Food and Drug Administration. GRAS Notice 956: Baciilus subtilis PLSSC (ATCC SD 7280) [Internet]. Silver Spring: FDA; 2021 [cited 2025 D
  40. Turck D, Bresson JL, Burlingame B, et al. Safety of the fermented soybean extract NSK-SD® as a novel food pursuant to Regulation (EC) No 258/97. EFSA J. 2016;14(7):4541.
  41. F.M. Co. Farmaceutica Milanese. Nattokinase NSK-SD®: Authorized Novel Food Ingredient [Internet]. Milan: Cofamispa; 2020 [cited 2025 Dec 22]. Available from: httpps://www.cofamispa.it/en/prodotti/nattokinase-nsk-sd/
  42. Gallelli G, Di Mizio G, Palleria C, et al. Data on the safety and efficacy of nattokinase in patients with vascular risk factors. Nutrients. 2021;13(6):203
  43. Lampe BJ, English JC. Toxicological assessment of nattokinase derived from Bacillus subtilis natto Chem Toxicol. 2016;88:87–99.
  44. Li X, et al. Nattokinase supplementation and cardiovascular risk factors: A systematic review and meta-analysis. Front Cardiovasc Med. 2023;10:11266782.
  45. Ren N, Chen H, Li Y, et al. Effective management of atherosclerosis progress and hyperlipidemia with nattokinase: A clinical study with 1,062 participants. Front Cardiovasc Med. 2022;9:964977.
  46. Wu DJ, Lin CS, Lee MY. Lipid-lowering effect of nattokinase in patients with primary hypercholesterolemia. Acta Cardiol Sin. 2009;25:26–3
  47. Kim JY, Gum SN, Paik JK, et al. Effects of nattokinase on blood pressure: a randomized, controlled trial. Hypertens Res. 2008;31(8):1583–1588.
  48. Ren N, McGowan EM, Chen H. Nattokinase attenuates endothelial inflammation through the activation of SRF and THBS1 and potentially slows atherosclerosis progression. Int J Biol Macromol. 2024;266(Pt 1):13133
  49. Bhatt TC, Mandaliya VB, Ibrahim M, Bhimani A, Detroja A, Koradiya J, et al. Multifaceted microbial enzyme nattokinase: a comprehensive review on therapeutics applications, production technologies and intellectual property landscape. Current Research in Biotechnology [Internet]. 2025 Jul 13;10:100316. Available from: https://www.sciencedirect.com/science/article/pii/S2590262825000474
  50. gov. 2025 [cited 2025 Dec 22]. Available from: https://www.clinicaltrials.gov/study/NCT06183307
  51. Effects of Nattokinase on Inflammation and Cardiovascular Risk Markers in Patients With Dyslipidemia [Internet]. DecenTrialz. 2024 [cited 2025 Dec 22]. Available from: https://decentrialz.com/clinical-trials/NCT06183307/effects-of-nattokinase-on-inflammation-and-cardiovascular-risk-markers-in-patients-with-dyslipidemia
  52. Nattokinase Atherothrombotic Prevention Study [Internet]. ctv.veeva.com. 2025 [cited 2025 Dec 22]. Available from: https://ctv.veeva.com/study/nattokinase-atherothrombotic-prevention-study
  53. Li D, Hou L, Hu M, Gao Y, Tian Z, Fan B, et al. Recent Advances in Nattokinase-Enriched Fermented Soybean Foods: A Review. Foods [Internet]. 2022 Jan 1;11(13):1867. Available from: https://www.mdpi.com/2304-8158/11/13/1867/htm
  54. Li Y, Zhu W, Chen L, Tang X, Ma A, Ma Y, et al. Modification of the active centre of nattokinase to enhance its thermostability using a strategy based on molecular dynamics simulation, steered dynamics simulation, and conservative prediction. Frontiers in Nutrition. 2024 Nov 14;11.