eng International Academy of Ecology and Environmental Sciences Network Pharmacology 2415-1084 2028-6-1 13 1-2 1 26 1 article WenJun Zhang 1 2 School of Life Sciences, Sun Yat-sen University, Guangzhou, China Nattokinase (NK), a potent fibrinolytic serine protease derived from the traditional Japanese fermented soybean food natto, has garnered substantial scientific interest over the past four decades due to its remarkable cardioprotective and thrombolytic properties. First isolated and characterized in the 1980s, this enzyme (EC 3.4.21.62), also known as subtilisin NAT, is produced during the fermentation of soybeans by Bacillus subtilis var. natto. This comprehensive review synthesizes the current body of scientific literature on nattokinase, encompassing its historical discovery, molecular structure, physicochemical properties, extraction and purification methodologies, pharmacokinetic profile, and multifaceted pharmacological mechanisms. Particular emphasis is placed on the enzyme's established fibrinolytic and antithrombotic activities, its emerging antihypertensive, anti-inflammatory, antioxidant, lipid-modulating, and neuroprotective effects, as well as its potential applications in respiratory health and the management of COVID-19-associated coagulopathy. A critical appraisal of clinical trial evidence, including randomized controlled trials evaluating nattokinase alone and in combination with other nutraceuticals, is presented alongside an analysis of safety data from toxicological assessments. The review further examines the current landscape of quality control standardization, regulatory considerations, and the challenges posed by inconsistent manufacturing practices. Finally, the review identifies critical knowledge gaps, discuss the limitations of existing research, and propose future research directions to fully elucidate the therapeutic potential of this promising natural enzyme in the prevention and adjunctive management of cardiovascular, neurodegenerative, and other non-communicable diseases. http://www.iaees.org/publications/journals/np/articles/2028-13(1-2)/Nattokinase.pdf nattokinase subtilisin NAT fibrinolytic enzyme cardiovascular disease thrombolysis hypertension anti-inflammatory antioxidant Bacillus subtilis var. natto clinical trial fermentation