LDHA- Mediated Histone Lactylation Promotes the Nonalcoholic Fatty Liver Disease Progression Through Targeting The METTL3/ YTHDF1/SCD1 m6A Axis

Nonalcoholic fatty liver disease (NAFLD) is characterized by elevated hepatic lipids caused by nonalcoholic factors, where histone lactylation is lately discovered as a modification driving disease progression. This research aimed to explore the role of histone 3 lysine 18 lactylation (H3K18lac) in NAFLD progression using a high-fat diet (HFD)-treated mouse model and free fatty acids (FFA)-treated L-02 cell lines. Lipids accumulation was screened via Oil Red O staining, real-time quantitative polymerase chain reaction (RT-qPCR), western blotting, and commercially available kits. 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. Keywords: Nonalcoholic fatty liver disease, LDHA, METTL3, YTHDF1, Histone lactylation.