SENP3 loss in biliary tract cancer chemoresistance: substrate-specific control of fatty acid oxidation and mitophagy

Chemoresistance limits the benefit of first-line therapy in advanced biliary tract cancer (BTC); the mechanisms reviewed here were identified in models of acquired resistance to gemcitabine, a core component of combination regimens. Recent studies implicate loss of small ubiquitin-like modifier (SUMO)-specific peptidase 3 (SENP3) in gemcitabine resistance through distinct upstream routes: METTL3-mediated N6-methyladenosine (m6A) modification and YTHDF2-dependent decay of SENP3 mRNA in intrahepatic cholangiocarcinoma (ICC), and increased proteasomal degradation of SENP3 in gemcitabine-resistant gallbladder cancer (GBC) cells with reduced reactive oxygen species (ROS). In ICC models, SENP3 loss promotes stabilization of hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha (HADHA) through proposed SUMOylation–ubiquitination crosstalk involving K309 and K531, accompanied by enhanced fatty acid oxidation (FAO) and lipophagy-associated lipid mobilization. Trimetazidine attenuates the resistant phenotype in preclinical models, although HADHA-specific drug action has not been established. In GBC models, SENP3 loss increases SUMOylation of Reptin (RUVBL2) at K456, redirecting Reptin to the nucleus, where it upregulates PTEN-induced kinase 1 (PINK1) and sustains a mitophagy–ROS feedback loop. CB-6644, an RUVBL1/2 ATPase inhibitor, enhances gemcitabine sensitivity and suppresses PINK1-associated mitophagy in GBC cells; the combination also showed antitumor activity in xenograft models, without establishing specific inhibition of Reptin K456 SUMOylation. This cross-substrate comparison reveals distinct protein-stability and subcellular-localization outcomes downstream of SENP3 loss and identifies substrate selectivity, potential FAO–mitophagy interactions, and clinical predictive utility as key questions for future investigation. Whether the two mechanisms coexist or interact within the same tumor remains untested.