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It plays a crucial role in immune cell development and is implicated in a range of pathological conditions. Nevertheless, the precise role of m6A in LPS-induced macrophage inflammatory responses remains elusive. In the present study, we investigated the role of the m6A writer Zc3h13 in LPS-induced liver inflammation. Macrophages, which are vital components of the immune system, play critical roles in liver injury. Our results demonstrate that Zc3h13 is highly expressed in liver macrophages during LPS-induced liver injury and is integral to the regulation of inflammatory factor expression and macrophage polarization. In vivo experiments reveal that knockdown of Zc3h13 alleviates LPS-induced liver inflammation in C57BL\/6 murine models. In vitro, Zc3h13 silencing in LPS-stimulated macrophages diminishes m6A methylation, attenuates inflammation, and promotes macrophage polarization from the proinflammatory to anti-inflammatory phenotype. Furthermore, Zc3h13 silencing stabilizes Spic mRNA in an m6A-dependent manner, thereby inhibiting NF-\u03baB pathway activation and alleviating inflammation. Notably, co-silencing of Spic and Zc3h13 reversed the inhibitory effects of Zc3h13 knockdown on inflammatory factor expression and NF-\u03baB pathway activation. In conclusion, our study suggests that Zc3h13 silencing alleviates LPS-induced liver injury through regulation of the NF-\u03baB pathway in macrophages.<\/jats:p>","DOI":"10.1093\/jimmun\/vkag034","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T09:56:34Z","timestamp":1773827794000},"source":"Crossref","is-referenced-by-count":2,"title":["Silencing of Zc3h13 attenuates LPS-induced inflammatory response in macrophages via m6A-dependent stabilization of Spic mRNA"],"prefix":"10.1093","volume":"215","author":[{"given":"Yaoyun","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Microbiology and Parasitology, Anhui Provincial Laboratory of Pathogen Biology, School of Basic Medical Sciences, Anhui Medical University , Hefei, Anhui,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunai","family":"Zhan","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Parasitology, Anhui Provincial Laboratory of Pathogen Biology, School of Basic Medical Sciences, Anhui Medical University , Hefei, Anhui,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Parasitology, Anhui Provincial Laboratory of Pathogen Biology, School of Basic Medical Sciences, Anhui Medical University , Hefei, Anhui,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Parasitology, Anhui Provincial Laboratory of Pathogen Biology, School of Basic Medical Sciences, Anhui Medical University , Hefei, Anhui,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Long","family":"Mei","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Parasitology, Anhui Provincial Laboratory of 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