<p>Liver cancer is the leading cause of cancer deaths worldwide and is the only cancer type among the five deadliest cancers with an increasing incidence each year. The prognosis of liver cancer is poor and no effective treatment for this cancer to date. Arsenic sulfide has been found to be effective in the treatment of hematological malignancies but its therapeutic outcomes and associated mechanisms in liver cancer remain unknown. In this study, we found that arsenic sulfide treatment could effectively inhibit the proliferation, migration and promotion of apoptosis of hepatoma cell lines, and remarkably alleviated the progression of hepatocellular carcinoma in mouse models. Transcriptomic analysis of the HepG2 cell line treated with arsenic sulfide showed that arsenic sulfide inhibited the proliferation of hepatoma cells by inhibiting the expression of Triacylglycerol and Lipid Catabolism Deficient 1 (TLCD1), thereby alleviating the malignant progression of hepatocellular carcinoma. This study provides a molecular basis for arsenic sulfide in the treatment of liver cancer.</p>