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We analyzed TNFAIP3 expression in diet-induced MASLD mouse models using public transcriptomic data. In vitro, we investigated the effects of TNFAIP3 overexpression and knockdown in HepG2 cells on lipid accumulation, autophagy, and key metabolic pathways. In vivo, a high-fat diet-induced mouse model was used to validate the protective role of TNFAIP3. TNFAIP3 was consistently upregulated in the livers of various MASLD mouse. Overexpression of TNFAIP3 in HepG2 cells reduced lipid droplet accumulation, whereas knockdown aggravated lipid deposition. TNFAIP3 enhanced autophagy by stabilizing ATG4B, and this effect was autophagy-dependent. In vivo, TNFAIP3 overexpression alleviated hepatic steatosis, improved insulin sensitivity, and modulated lipid metabolism-associated pathways. These effects were reversed by autophagy inhibitors. Furthermore, TNFAIP3 upregulation was driven by NF-\u03baB signaling, as inhibition of NF-\u03baB decreased TNFAIP3 levels. The NF-\u03baB\u2013TNFAIP3 axis regulates hepatic lipid metabolism and protects against liver injury in MASLD, primarily through autophagy. These findings suggest that TNFAIP3 could serve as a potential therapeutic target for MASLD and other metabolic liver diseases.<\/jats:p>","DOI":"10.1038\/s41420-026-03310-9","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T07:16:05Z","timestamp":1787642165000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The NF-\u03baB-TNFAIP3 axis attenuates MASLD via activation of hepatocyte autophagy"],"prefix":"10.1038","volume":"12","author":[{"given":"Qun","family":"Sun","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guixin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huixiang","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangwei","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Long","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2609-4223","authenticated-orcid":false,"given":"Jinghui","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,25]]},"reference":[{"key":"3310_CR1","doi-asserted-by":"publisher","first-page":"S32","DOI":"10.3350\/cmh.2024.0431","volume":"31","author":"ZM Younossi","year":"2025","unstructured":"Younossi ZM, Kalligeros M, Henry L. 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