Pachymic acid exhibits synergistic antitumor efficacy with lenvatinib in hepatocellular carcinoma by targeting PPARγ to inhibit glycolysis.

Lenvatinib is a first-line treatment for hepatocellular carcinoma (HCC), though drug resistance may develop with long-term use. to investigate the potential of pachymic acid to enhance lenvatinib's anti-tumor efficacy. HepG2 and LM3 cells were exposed to pachymic acid and/or lenvatinib. Cell proliferation was evaluated using colony formation assays and flow cytometry analysis of apoptosis. Cell invasion was evaluated using wound healing assays and transwell assays. Glucose consumption, lactate production and glycolysis-related protein expression were measured to evaluate aerobic glycolysis status. Tumor-bearing experiments in nude mice were conducted to verify pachymic acid's influence on HCC. Twenty µmol/L pachymic acid substantially inhibited the apoptosis rate (8.5% versus 15.2%, p < 0.001), wound healing rate (59.3% versus 31.0%, p < 0.001), glucose consumption (5.3 µmol/L versus 3.4 µmol/L, p < 0.001) and lactate production (0.7 µmol/L versus 0.3 µmol/L, p < 0.001) in HepG2 cells. Similar results were observed in LM3 cells. Peroxisome proliferator-activated receptor gamma (PPARγ) could be its molecular target that intervenes in aerobic glycolysis of HCC. Notably, pachymic acid exhibited synergistic antitumor efficacy with lenvatinib in both in vitro (cell survival rate: 53.3% in the lenvatinib group versus 33.3% in the pachymic acid + lenvatinib group, p < 0.001) and in vivo models (tumor volume: 483.0 mm3 in the lenvatinib group versus 357.5 mm3 in the pachymic acid + lenvatinib group, p < 0.01). These findings provide a novel perspective, showing that pachymic acid suppresses aerobic glycolysis in HCC by targeting PPARγ. Furthermore, combining pachymic acid and lenvatinib was discovered to produce a synergistic antitumor effect.