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Nicotinamide phosphoribosyl transferase (NAMPT) and six-transmembrane epithelial antigen of the prostate 4 (STEAP4) are integral regulators in various metabolic disorders. This study investigates the role and molecular mechanisms of NAMPT in NAFLD pathogenesis. We found that inhibiting NAMPT or silent information regulator 1 (SIRT1) exacerbates liver steatosis and impairs hepatic antioxidant defenses in high-fat diet (HFD)-induced obese mice, while reducing STEAP4 expression in liver tissues, suggesting that NAMPT and SIRT1 are pivotal in NAFLD progression and may regulate STEAP4. The role of NAMPT in SIRT1 expression involves nicotinamide adenine dinucleotide synthesis. Our results indicate that inhibiting SIRT1\u2019s deacetylase activity impairs CCAAT\/enhancer-binding protein \u03b2 (C\/EBP\u03b2) deacetylation and consequently its function. Additionally, STEAP4, previously identified as a C\/EBP\u03b2 target, can upregulate the expression and nuclear translocation of NF-E2-related factor 2 (NRF2) to combat oxidative stress in NAFLD. This study confirms that NAMPT ameliorates NAFLD via the SIRT1\u2013C\/EBP\u03b2\u2013STEAP4\u2013NRF2 signaling axis in HFD-induced obese mice, proposing a novel strategy for the prevention and treatment of NAFLD.<\/jats:p>","DOI":"10.1093\/jmcb\/mjaf045","type":"journal-article","created":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T12:34:16Z","timestamp":1764592456000},"source":"Crossref","is-referenced-by-count":0,"title":["NAMPT improves high-fat diet-induced nonalcoholic fatty liver disease (NAFLD) via the SIRT1\u2013C\/EBP\u03b2\u2013STEAP4\u2013NRF2 axis"],"prefix":"10.1093","volume":"17","author":[{"given":"Jingwu","family":"Zhao","sequence":"first","affiliation":[{"name":"College of Animal Science and Technology & College of Veterinary Medicine, Huazhong Agricultural University , Wuhan 430070 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qinjin","family":"Li","sequence":"additional","affiliation":[{"name":"College of Animal Sciences, Fujian Agriculture and Forestry University , Fuzhou 350002 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology & College of Veterinary Medicine, Huazhong Agricultural University , Wuhan 430070 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bingbing","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology & College of Veterinary Medicine, Huazhong Agricultural University , Wuhan 430070 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sisi","family":"Gui","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology & College of Veterinary Medicine, Huazhong Agricultural University , Wuhan 430070 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yazhen","family":"Zheng","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology & College of Veterinary Medicine, Huazhong Agricultural University , Wuhan 430070 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5717-849X","authenticated-orcid":false,"given":"Xiaodong","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology & College of Veterinary Medicine, Huazhong Agricultural University , Wuhan 430070 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,12,1]]},"reference":[{"key":"2026042411163605900_bib1","doi-asserted-by":"crossref","first-page":"174","DOI":"10.3390\/antiox10020174","article-title":"Role of oxidative stress in the pathogenesis of non-alcoholic fatty liver disease: implications for prevention and therapy","volume":"10","author":"Arroyave-Ospina","year":"2021","journal-title":"Antioxidants"},{"key":"2026042411163605900_bib2","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1007\/s00018-018-2947-0","article-title":"Molecular pathways of nonalcoholic fatty liver disease development and progression","volume":"76","author":"Bessone","year":"2019","journal-title":"Cell. 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