This study reports the isolation and characterization of six novel tetrahydroxanthone derivatives, paraconixanthones A - F (1-6), a new diphenyl ether (7), and thirteen known compounds (8-20) from the endophytic fungus Paraconiothyrium sp. AC31. The chemical structures were elucidated using NMR, MS, X-ray diffraction, and ECD analyses. Paraconixanthones A and B (1 and 2) represent the first examples of tetrahydroxanthone-benzoate dimers, suggesting a unique biosynthetic pathway. Compound 12 exhibited potent anti-proliferative activity against HepG2 hepatocellular carcinoma cells (IC50 = 1.19 μM), outperforming the standard therapy lenvatinib. Mechanistic studies revealed that compound 12 inhibits PARP1, leading to DNA damage, ROS accumulation, and caspase-3/GSDME-mediated pyroptosis. Additionally, it induces intrinsic apoptosis through BAX/BCL-2 modulation and caspase-7 activation. Meanwhile, GSDME deficiency treated with 12 exhibited the increased levels of PARP1 and caspase-3, supporting the cell death induced by 12 shifted from pyroptosis to apoptosis. These findings highlight the therapeutic potential of tetrahydroxanthones as selective agents targeting multiple cell death pathways in hepatocellular carcinoma, expanding the scope of natural product-based anti-cancer strategies.