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While primarily affecting avian species, H5N1 has repeatedly breached species barriers, infecting mammals including humans, minks, seals, and cattle. This review synthesizes current knowledge on the molecular mechanisms underpinning H5N1's host adaptation, focusing on key mutations in viral proteins\u2010such as hemagglutinin (HA), neuraminidase (NA), and polymerase subunits (PB2)\u2010which boost binding affinity to human\u2010type receptors, increase replicative efficiency in mammalian cells, and facilitate immune evasion. Critical mutations, including HA\u2010Q226L, HA\u2010T199I, PB2\u2010E627K, and NA\u2010H274Y, are discussed in detail, highlighting their roles in altering receptor specificity, promoting antiviral resistance, and expanding viral tropism. The paper also outlines epidemiological trends, global dissemination patterns driven by migratory birds and trade, and current strategies for prevention and control, including antiviral therapeutics and vaccine development. Ultimately, this comprehensive analysis underscores the urgent need for continued surveillance, broad\u2010spectrum countermeasures, and international collaboration to reduce the pandemic risk posed by H5N1.<\/jats:p>","DOI":"10.1002\/ggn2.202500051","type":"journal-article","created":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T06:35:06Z","timestamp":1768199706000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Evolution of H5N1 Cross\u2010Species Transmission: Adaptive Mutations Driving Avian\u2010to\u2010Human Infection"],"prefix":"10.1002","volume":"7","author":[{"given":"Wenxin","family":"Man","sequence":"first","affiliation":[{"name":"College of Life Science Northeast Forestry University  Harbin China"},{"name":"State Key Laboratory of Synthetic Biology Tianjin University Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Du","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Synthetic Biology Tianjin University Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Synthetic Biology Tianjin University Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zehan","family":"Pang","sequence":"additional","affiliation":[{"name":"College of Life Science and Technology Beijing University of Chemical Technology  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyan","family":"Zhu","sequence":"additional","affiliation":[{"name":"College of Biology and Brewing Engineering Taishan University  Taian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bixia","family":"Hong","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Synthetic Biology Tianjin University Tianjin China"},{"name":"School of Basic Medical Science State Key Laboratory of Respiratory Disease Guangzhou Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhichao","family":"Xu","sequence":"additional","affiliation":[{"name":"College of Life Science Northeast Forestry University  Harbin China"},{"name":"State Key Laboratory of Synthetic Biology Tianjin University Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5007-2158","authenticated-orcid":false,"given":"Huahao","family":"Fan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Synthetic Biology Tianjin University Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,1,11]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00705-016-3137-8"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1086\/314515"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.3201\/eid0502.990202"},{"key":"e_1_2_8_5_1","volume-title":"Cumulative Number of Confirmed Human Cases for Avian Influenza A(H5N1) Reported to WHO","year":"2025"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00430-007-0042-5"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.med.57.121304.131333"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000161"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11427-009-0115-3"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0013575"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1017\/S0950268809990495"},{"key":"e_1_2_8_12_1","first-page":"3264","article-title":"Bayesian Inference Reveals Host\u2010Specific Contributions to the Epidemic Expansion of Influenza A H5N1","volume":"32","author":"Trov\u00e3o N. 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