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Existing antivirals suffer from numerous limitations, such as the frequent emergence of drug resistance and inconvenient administration, highlighting the urgent need for the development of next-generation anti-influenza agents. As a core component of the RNA-dependent RNA polymerase (RdRp) complex, the PB2 subunit mediates cap binding in the cap-snatching process, a prerequisite for viral mRNA transcription. Owing to its indispensable biological roles, high sequence conservation, and distinct structural differences from host proteins, PB2 serves as an attractive therapeutic target for antiviral drug development. Recently, the approval of onradivir, the first-in-class PB2 inhibitor, has not only validated the scientific rationale and feasibility of drug discovery targeting the PB2 subunit but also underscored the considerable clinical potential of this novel class of agents. In this review, we systematically summarize the research advances in PB2 inhibitors and discuss the challenges and prospects for their broader clinical application, with the aim of providing new insights into the development of novel anti-influenza drugs.<\/jats:p>","DOI":"10.1021\/acsinfecdis.6c00541","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T22:02:04Z","timestamp":1785880924000},"page":"2572-2592","source":"Crossref","is-referenced-by-count":0,"title":["Inhibitors of\nthe Influenza Virus Polymerase Basic\n2 (PB2): Recent Advances and Future Perspectives"],"prefix":"10.1021","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-7320-2838","authenticated-orcid":true,"given":"Xinru","family":"Zhang","sequence":"first","affiliation":[{"name":"Qingdao University , , ,","place":["Qingdao, China, 266021"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4051-9329","authenticated-orcid":true,"given":"Heng","family":"Jia","sequence":"additional","affiliation":[{"name":"Qingdao University , , ,","place":["Qingdao, China, 266021"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianglong","family":"Wang","sequence":"additional","affiliation":[{"name":"Qingdao University , , ,","place":["Qingdao, China, 266021"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-0748-0244","authenticated-orcid":true,"given":"Han","family":"Ju","sequence":"additional","affiliation":[{"name":"Qingdao University , , ,","place":["Qingdao, China, 266021"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingxin","family":"Dong","sequence":"additional","affiliation":[{"name":"Qingdao University , , ,","place":["Qingdao, China, 266021"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"2026081410073492900_cit1","unstructured":"World Health Organization.\n          \n          Influenza (seasonal). https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/influenza-(seasonal)."},{"issue":"4","key":"2026081410073492900_cit2","doi-asserted-by":"publisher","first-page":"810","DOI":"10.3390\/molecules26040810","article-title":"Development and Effects\nof Influenza\nAntiviral Drugs","volume":"26","author":"Yin","year":"2021","journal-title":"Molecules"},{"issue":"1","key":"2026081410073492900_cit3","doi-asserted-by":"publisher","first-page":"1721","DOI":"10.1038\/s41467-022-29402-5","article-title":"Human seasonal\ninfluenza\nunder COVID-19 and the potential consequences of influenza lineage\nelimination","volume":"13","author":"Dhanasekaran","year":"2022","journal-title":"Nat. Commun."},{"issue":"20","key":"2026081410073492900_cit4","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202410513","article-title":"Immunity Debt for\nSeasonal Influenza After the COVID-19\nPandemic and as a Result of Nonpharmaceutical Interventions: An Ecological\nAnalysis and Cohort Study","volume":"12","author":"Chen","year":"2025","journal-title":"Adv. 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