Histone lactylation-driven YTHDC1 promotes hepatocellular carcinoma progression via lipid metabolism remodeling

Lipid metabolism reprogramming is critical for the initiation and progression of hepatocellular carcinoma (HCC). However, how the dysregulation of lipid metabolism contributes to HCC development remains largely unknown. Here, we report that the m⁶A reader YTHDC1-mediated epigenetic regulation of the long noncoding RNA NEAT1 activates stearoyl-CoA desaturase (SCD)-associated lipid metabolic processes during HCC progression. Mechanistically, histone lactylation in HCC induces increased expression of YTHDC1, increasing the stability of m⁶A-modified NEAT1. The histone acetyltransferase p300 is then recruited by NEAT1 and activates SCD by increasing the level of histone acetylation at the SCD promoter, thus facilitating HCC progression via hepatocellular lipid metabolism remodeling. Taken together, these discoveries suggest a close link between the epigenetic machinery and lipid metabolic abnormalities, which promotes cancer progression.