TRIM46 drives lung adenocarcinoma progression by stabilizing PRDX1 via SUMOylation

Abstract

Lung adenocarcinoma (LUAD) is one of the major subtypes of non-small cell lung cancer (NSCLC), but the molecular mechanisms underlying LUAD initiation and progression remain incompletely understood. In the present study, we identified TRIM46 as a key driver of LUAD progression. TRIM46 is significantly overexpressed in LUAD tissues, and its high expression correlates with advanced disease and poor patient prognosis. Functional studies using genetic manipulation in vitro, patient-derived organoids, and xenograft models have demonstrated that TRIM46 promotes tumor cell proliferation, migration, and survival. Mechanistically, we discovered that TRIM46 does not act through its canonical E3 ubiquitin ligase activity but instead recruits the SUMO-conjugating enzyme UBC9 to catalyze SUMOylation of the antioxidant enzyme PRDX1 at lysine109. This modification reduces K48-linked polyubiquitination of PRDX1 by ZNF598, thereby stabilizing PRDX1. Stabilized PRDX1 significantly suppresses lipid peroxidation and ferroptosis, thereby triggering the progression of LUAD and conferring resistance to cisplatin. Furthermore, we identified ZNF143 as the upstream transcription factor responsible for TRIM46 overexpression. Collectively, our findings delineate a ZNF143-TRIM46-PRDX1 signaling axis that promotes LUAD malignancy and chemoresistance by stabilizing PRDX1 via a novel SUMOylation switch and inhibiting ferroptosis, suggesting that this pathway is a promising therapeutic target for overcoming cisplatin resistance.