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Similarly, molecular mechanism was analyzed using immunoprecipitation (IP), dual-luciferase reporter assay, and RNA decay assay. Results indicated that FFA upregulated lactate dehydrogenase A (LDHA) and H3K18lac levels in L-02 cells. Besides, LDHA-mediated H3K18lac was enriched on the proximal promoter of methyltransferase 3 (METTL3), translating into an increased expression. Moreover, METTL3 or LDHA knockdown relieved lipid accumulation, decreased total cholesterol (TC) and triglyceride (TG) levels, and downregulated lipogenesis-related proteins in FFA-treated L-02 cell lines, in addition to enhancing the m6A and mRNA levels of stearoyl-coenzyme A desaturase 1 (SCD1). The m6A modification of SCD1 was recognized by YTH N6-methyladenosine RNA binding protein F1 (YTHDF1), resulting in enhanced mRNA stability. LDHA was found to be highly expressed in HFD-treated mice, where knocking down LDHA attenuated HFD-induced hepatic steatosis. These findings demonstrated that LDHA-induced H3K18lac promoted NAFLD progression, where LDHA-induced H3K18lac in METTL3 promoter elevated METTL3 expression, thereby promoting m6A methylation and stabilizing SCD1 via a YTHDF1-dependent manner.<\/jats:p>","DOI":"10.33549\/physiolres.935289","type":"journal-article","created":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T09:26:11Z","timestamp":1738142771000},"page":"985-999","source":"Crossref","is-referenced-by-count":21,"title":["LDHA- Mediated Histone Lactylation Promotes the Nonalcoholic Fatty Liver Disease Progression Through Targeting The METTL3\/ YTHDF1\/SCD1 m6A Axis"],"prefix":"10.33549","author":[{"given":"J","family":"Meng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, First Hospital of Shanxi Medical University, No.85 Jiefang South Road, Taiyuan, Shanxi 030000, China. ljc2891@163.com"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"19169","published-online":{"date-parts":[[2024,12,31]]},"reference":[{"key":"ref0","doi-asserted-by":"publisher","unstructured":"Abdelmalek MF. 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