Sodium butyrate induces cuproptosis by regulating the HDAC1-SLC31A1 axis in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the primary type of liver malignancy, which stands as the third leading contributor to cancer-related death worldwide. Sodium butyrate (NaB), a gut microbiota-derived short-chain fatty acid with known anticancer activity, remains poorly understood in HCC. This study aimed to elucidate the effects and underlying mechanisms of NaB-induced cuproptosis in HCC cells. 200 mg/kg NaB inhibits HCC tumor growth by 73.9% and induced a 1.83- and 6.83-fold increase in the Cu²⁺ content and SLC31A1 protein expression, respectively. Furthermore, 5 mmol/L NaB inhibits cell viability by 35.4% and induced a 1.52-, 2.20-, 7.96-, 2.34-, and 2.24-fold increase in the cell number in G1 phase, Cu²⁺ content and protein expression of SLC31A1, FDX1 and lipoic DLAT, respectively. NaB inhibits viability and cell cycle progression and promotes cuproptosis in HCC cells, which were revised by SLC31A1. NaB induces SLC31A1 expression by inhibiting HDAC1-induced decrease in the levels of H3K27ac, thus inhibiting HepG2 cell growth and promoting cuproptosis. SLC31A1 mRNA is positively correlated with Cu²⁺ concentration, while HDAC1 mRNA is negatively correlated with both Cu²⁺ concentration and SLC31A1 mRNA in patients with HCC. In conclusion, our findings indicate that NaB inhibits the HCC cell growth by targeting HDAC1-SLC31A1 axis-dependent cuproptosis.