Disrupting CARMA3 Signaling with Triptolide Reverses Sorafenib Resistance in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and the second leading cause of cancer-related mortality. Prognostic prediction in HCC is complicated by its heterogeneity, and current treatment strategies are limited to surgical resection and targeted therapies. Sorafenib, a multi-kinase inhibitor and the first-line systemic therapy for advanced HCC, offers modest survival benefits and often induces resistance during long-term administration. Therefore, elucidating the molecular mechanisms of drug resistance is critical for improving therapeutic outcomes. Triptolide is a diterpenoid triepoxide extracted from the traditional Chinese herb Tripterygium wilfordii, exhibits potent anti-inflammatory and anti-neoplastic properties in various cancer types. CARMA3 (CARD10), a membrane-associated scaffold protein, has recently emerged as a key oncogenic regulator in solid tumors. This study demonstrates that CARMA3 contributes to chemoresistance in HCC and that triptolide enhances chemosensitivity by downregulating CARMA3 expression and promoting reactive oxygen species (ROS) accumulation. Our findings suggest that triptolide functions as a chemosensitizing agent by modulating CARMA3-mediated ROS accumulation and ferroptosis resistance, offering a novel therapeutic strategy for overcoming HCC drug resistance.