Pachymic Acid Promotes PANoptosis and Donafenib Efficacy in Hepatocellular Carcinoma by Activating XDH-Mitochondrial ROS Axis

Methods

The antitumor activity of PA was assessed using the HepG2 HCC cell line. Key molecular targets of PA were identified by integrating transcriptomic sequencing with network pharmacology approaches. The potential molecular mechanisms underlying PA’s anti-HCC effects were investigated in vitro through knockdown and overexpression of key target molecules.

The in vivo efficacy of PA alone and in combination with donafenib was evaluated using a xenograft model, and detailed mechanistic studies were conducted using specific activators, inhibitors, and lentiviral transfection.Results: Our results demonstrate that the anti-HCC activity of PA is associated with PANoptosis. PA promotes the release of mitochondrial reactive oxygen species (mtROS) by upregulating Xanthine dehydrogenase (XDH) expression, ultimately triggering PANoptosis in HCC cells.

Furthermore, combined treatment with PA and donafenib significantly enhanced the sensitivity of HepG2 cells and xenograft tumors to donafenib, likely attributable to PA-mediated activation of the XDH–mitochondrial ROS axis.Conclusion: PA induces PANoptosis in HCC by activating the XDH–mitochondrial ROS axis, thereby suppressing HCC proliferation, promoting apoptosis, and enhancing HCC sensitivity to donafenib.