Abstract
CD147 has emerged as a promising tumor-specific therapeutic target. Identifying small-molecule inhibitors that promote its proteolysis represents a critical step toward advancing clinical translation, while elucidating its mechanisms of action could further accelerate this process. In this study, we identify dracorhodin perchlorate (DP) as a potent CD147 inhibitor that induces autophagy-dependent degradation. DP significantly inhibits cell proliferation and enhances sensitivity to gemcitabine in pancreatic cancer cells. Mechanistically, CD147 inhibition upregulates acyl-CoA synthetase long-chain family member 4 (ACSL4) expression through H3K9 lactylation and suppresses the sterol regulatory element-binding protein 1 (SREBP1)/stearoyl-CoA desaturase-1 (SCD1) signaling pathway, collectively disrupting the balance of polyunsaturated and monounsaturated fatty acids, ultimately triggering ferroptosis. The combination of DP and gemcitabine demonstrates remarkable synergistic anti-tumor effects in orthotopic xenograft models, spontaneous KPC mouse models, and patient-derived organoid (PDO) and xenograft (PDX) models. In conclusion, this study reveals a mechanism by which CD147 regulates ferroptosis and supports combining DP with gemcitabine as a therapeutic strategy to improve patient outcomes in pancreatic ductal adenocarcinoma.