Given the rising incidence and mortality rates of cancer, the development of highly effective, low-toxicity therapeutics is critical. Xanthones, a class of natural secondary metabolites, are notable for their distinct structure and exhibit promising antitumor activity, underscoring their potential as scaffolds for drug design. Sulfur heterocycles are also valuable in the development of bioactive small molecules. Therefore, we explored the introduction of sulfur in the core structure of xanthones, leading to the synthesis of a series of sulfur-containing tetrahydroxanthones. The in vitro cytotoxicity of these compounds was evaluated using the CCK8 assay, revealing that several derivatives exhibit anti-proliferative effects against HepG2 cells. Among them, compound 4k displayed potent inhibitory activity with an IC