Lactate promotes cholesterol uptake by facilitating SCARB1 expression through histone H3K18 lactylation

Metabolic reprogramming supports the proliferation of cancer cells under hypoxic stress, including enhanced glycolysis and altered fatty acid metabolism. However, the mechanism underlying its regulation of cholesterol metabolism remains incompletely understood. Here, we show that lactate-induced cholesterol accumulation activates mammalian target of rapamycin complex 1 (mTORC1) signaling under hypoxic conditions, thereby promoting hepatocellular carcinoma (HCC) progression. Mechanistically, lactate upregulates scavenger receptor class B type 1 (SCARB1) expression by enhancing histone H3 lysine 18 lactylation (H3K18la), leading to increased cholesterol levels. We furthermore demonstrate that SCARB1-mediated cholesterol uptake is essential for the activation of mTORC1, which promotes tumor growth by preventing HCC cells from excessive autophagy. Importantly, analysis of clinical HCC samples showed a positive correlation between H3K18la and SCARB1 expression. Taken together, these findings provide novel insights into hypoxia-driven metabolic reprogramming and reveal a previously unrecognized connection between lactate and cholesterol metabolism, suggesting a potential innovative cancer therapy for HCC. Overall design: RNA-Seq profiling of Hep3B cells cultured under normoxia, hypoxia, hypoxia treated with oxamate sodium for 48 hours