SENP3 induced HADHA deSUMOylation enhances intrahepatic cholangiocarcinoma chemotherapy sensitivity via fatty acid oxidation.

Chemoresistance contributes to poor outcomes in patients with intrahepatic cholangiocarcinoma (ICC). This study aimed to explore the mechanisms underlying chemotherapy resistance and to develop strategies that can sensitize the chemotherapy. Patient derived organoids (PDOs) drug screening and Lipidomics profiling were performed to investigate the chemoresistance mechanism. Through multi-strategy analysis, we found that SENP3 enhanced chemotherapy sensitivity in a SUMO system dependent manner. Mechanistically, chemotherapy resistance increased METTL3 expression, which regulated SENP3 mRNA stability through YTHDF2-dependent m6A methylation modifications. SENP3 interacted with HADHA and catalyzed its deSUMOylation at two lysine residues. Specifically, SUMOylation and ubiquitination exhibited crosstalk at the same modification sites on HADHA, influencing its protein stability and, consequently, regulating fatty acid oxidation (FAO) levels. The physical interaction of SENP3, HADHA, and USP10 provides a novel molecular mechanism for the abnormal activation of FAO pathway. The lipid metabolism-targeting drug could be a promising therapeutic strategy for sensitizing ICC to chemotherapy.