SUCLG2 contributes to platinum resistance in lung adenocarcinoma through enhancing succinylation of GAC and glutamine metabolism.

Platinum-based drugs constitute first-line chemotherapy for lung adenocarcinoma (LUAD), yet resistance emerges in 50-70% of patients, representing a major clinical challenge. Synthetase GDP-forming subunit β (SUCLG2), the beta subunit of succinyl-CoA synthetase, is a key enzyme in the tricarboxylic acid (TCA) cycle. Using untargeted proteomic profiling, we identified SUCLG2 as a potential contributor of platinum resistance in LUAD. Further knockout of SUCLG2 significantly enhanced cellular sensitivity to platinum-based drugs. Mechanistically, using targeted metabolomics, we found that SUCLG2 conferred platinum resistance by promoting glutamine metabolism and facilitating the succinylation of glutaminase (GAC). This post‑translational modification enhanced GAC activity, thereby reducing ROS generation and suppressing apoptosis in LUAD cells. SUCLG2 was found to be highly expressed in both LUAD tissues and platinum-resistant cell lines. Consistent with cellular findings, animal experiments confirmed that elevated SUCLG2 expression critically contributes to platinum resistance in vivo. Our findings provide new insights into the molecular mechanisms underlying platinum resistance in LUAD and suggest novel therapeutic strategies.