Lactate-mediated cholesterol uptake promotes liver cancer progression via the SCARB1-autophagy axis

Metabolic reprogramming, including enhanced glycolysis and altered fatty acid metabolism, supports the proliferation of cancer cells under hypoxic stress. However, the mechanism underlying the regulation of cholesterol metabolism under hypoxic stress remains incompletely understood. Here, we report that lactate-induced cholesterol accumulation activates mammalian target of rapamycin complex 1 (mTORC1) signalling under hypoxic conditions, thereby promoting hepatocellular carcinoma (HCC) progression. Mechanistically, lactate upregulates scavenger receptor class B type 1 (SCARB1) expression by increasing histone H3 lysine 18 lactylation (H3K18la), leading to increased cholesterol levels. We further demonstrate that SCARB1-mediated cholesterol uptake is essential for the activation of mTORC1, which promotes tumour growth by preventing excessive autophagy in HCC cells. Importantly, analysis of clinical HCC samples reveals a positive correlation between H3K18la expression 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.