WenJun Zhang School of Life Sciences, Sun Yat-sen University, Guangzhou, China Network Biology ISSN 2220-8879 http://www.iaees.org/publications/journals/nb/online-version.asp 2027 17 1 20 45 International Academy of Ecology and Environmental Sciences Hong Kong 30 March 2026 28 April 2026 1 March 2027 hirudin thrombin inhibitor anticoagulant recombinant hirudin lepirudin desirudin bivalirudin pharmacology clinical trials Hirudin is a 65-amino acid polypeptide originally isolated from the salivary glands of the medicinal leech Hirudo medicinalis, represents the most potent and specific natural inhibitor of thrombin discovered to date. Since its initial characterization in the 1950s, hirudin has evolved from a scarce natural product to a clinically available recombinant anticoagulant, with multiple derivatives approved for therapeutic use including lepirudin, desirudin, and bivalirudin. This review provides a comprehensive analysis of hirudin's discovery history, molecular structure, physicochemical properties, extraction and purification methodologies, pharmacokinetics, and extensive pharmacological activities. Beyond its established role as an anticoagulant, emerging evidence demonstrates that hirudin possesses diverse bioactivities including anti-inflammatory, antioxidant, neuroprotective, anti-fibrotic, wound-healing, anti-tumor, and anti-hyperuricemic effects. Clinical experience with hirudin and its derivatives spans acute coronary syndromes, heparin-induced thrombocytopenia, venous thromboembolism prophylaxis, and other thrombotic disorders. However, challenges including narrow therapeutic index, bleeding risk, renal dependence, and immunogenicity continue to limit broader application. This review synthesizes current knowledge while identifying critical gaps requiring further investigation, including optimization of dosing strategies, development of safer derivatives, expansion of non-anticoagulant therapeutic applications, and elucidation of molecular mechanisms underlying recently discovered bioactivities. http://www.iaees.org/publications/journals/nb/articles/2027-17(1)/Hirudin.pdf