SIRT5-Mediated FDX1 Desuccinylation Confers Cuproptosis Resistance in Lung cancer

ABSTRACT: Cuproptosis, a copper-dependent cell death process induced by excessive copper, represents an emerging therapeutic strategy in oncology. However, tumor specific molecular pathways regulating this process remain poorly defined. Here, we demonstrate that copper levels are elevated in lung adenocarcinoma (LUAD), and LUAD cell lines exhibit increased resistance to cuproptosis. Mechanistically，elevated copper stress promotes expression of the desuccinylase SIRT5 while reducing global succinylation in LUAD cells. Furthermore, we found that SIRT5 is a critical mediator of cuproptosis through the desuccinylation modification on Ferredoxin1(FDX1) protein at Lys84. This modification triggers TRIM8-mediated ubiquitination, leading to FDX1 proteasomal degradation and enhanced cuproptosis resistance. These results reveal the important role of SIRT5 in LUAD cuproptosis resistance. Notably, combining the SIRT5 inhibitor MC3482 with the cuproptosis inducer Elesclomol-Cu synergistically suppresses tumor growth in vitro and in

ORGANISM(S): Homo Sapiens

SUBMITTER: Bentong Yu  

PROVIDER: PXD077292 | iProX | Fri Apr 17 00:00:00 BST 2026

REPOSITORIES: iProX