SENP3 loss in biliary tract cancer chemoresistance: substrate-specific control of fatty acid oxidation and mitophagy
Abstract
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.
Related
- Early metabolic remodeling of insulin sensitivity and substrate oxidation with lipoprotein changes at postoperative day 3 after sleeve gastrectomy
- Sex Differences in Substrate Oxidation During Incremental Exercise: An Exploratory Study on the Role of Body Composition.
- Defense and subversion: multilevel mitochondrial quality control and pathway‑specific mitophagy outcomes in Mycobacterium tuberculosis infection
- Long-term lactate ingestion and exercise training differentially modulate body composition, resting substrate metabolism, and tissue-specific metabolic remodeling in mice
- Segment-Specific Occlusion of Retrieved Plastic Biliary Stents: Direct Quantification and Microbial and Material Determinants.
BibTeX
@article{zheng2026senp3,
title = {{SENP3 loss in biliary tract cancer chemoresistance: substrate-specific control of fatty acid oxidation and mitophagy}},
author = {Wanxu Zheng and Shiji Xia and Wangdong Zhu and Guangye Zhang},
journal = {Frontiers in Pharmacology},
year = {2026},
month = nov,
doi = {10.3389/fphar.2026.2008205},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.2008205},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - SENP3 loss in biliary tract cancer chemoresistance: substrate-specific control of fatty acid oxidation and mitophagy
AU - Wanxu Zheng
AU - Shiji Xia
AU - Wangdong Zhu
AU - Guangye Zhang
PY - 2026
DA - 2026/11/06
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.2008205
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.2008205
AB - 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.
SN - 1663-9812
ER -