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Lentiviral-mediated knockdown and overexpression of TRA2A were employed to evaluate its effects on TXNIP expression, m6A modifications, and HIV-1 replication, while pyroptosis and inflammatory responses were assessed through LDH release assays, cytokine measurements, and analysis of the NLRP3\/Caspase-1\/GSDMD signaling pathway. Results showed significant downregulation of TRA2A in macrophages from HIV-1 patients, and TRA2A knockdown promoted viral replication while activating NLRP3\/Caspase-1\/GSDMD-mediated pyroptosis; mechanistically, TRA2A recognized m6A sites on TXNIP mRNA to reduce its stability, thereby inhibiting inflammasome activation, with these effects reversed by TRA2A overexpression or TXNIP\/pyroptosis inhibitors, confirming TRA2A\u2019s critical role in balancing antiviral defense and inflammation control. Collectively, TRA2A functions as an m6A regulator to balance antiviral defense and inflammation via the TXNIP-mediated NLRP3 pathway, establishing a novel regulatory axis and highlighting TRA2A as a potential dual-target therapeutic candidate.<\/jats:p>","DOI":"10.1038\/s41420-026-03236-2","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T03:30:19Z","timestamp":1782444619000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["TRA2A negatively regulates HIV-1-induced macrophage pyroptosis by mediating TXNIP expression in an m6A-dependent manner"],"prefix":"10.1038","volume":"12","author":[{"given":"Xing","family":"Tao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinming","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tongxue","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongfeng","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinlu","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ran","family":"Duan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiyi","family":"Lai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youjin","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinmiao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7688-4867","authenticated-orcid":false,"given":"Li","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7534-5124","authenticated-orcid":false,"given":"Hao","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4905-9348","authenticated-orcid":false,"given":"Junjun","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,26]]},"reference":[{"key":"3236_CR1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21816-x","volume":"12","author":"CA Jette","year":"2021","unstructured":"Jette CA, Barnes CO, Kirk SM, Melillo B, Smith AB 3rd, Bjorkman PJ, et al. 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