STING-driven mitochondrial metabolism reverses cisplatin resistance via MDH2 desuccinylation in non-small cell lung cancer

Abstract

Introduction: Cisplatin resistance is a major obstacle in the treatment of non-small cell lung cancer (NSCLC) and remains a leading cause of cancer-related deaths worldwide. This resistance substantially reduces the efficacy of cisplatin and highlights the need for innovative therapeutic strategies.

Objectives: To identify targets that reverse cisplatin resistance and clarify the underlying mechanisms of action.

Methods: The key protein stimulator of interferon gene (STING), involved in regulating cisplatin resistance in NSCLC, was identified through proteomics and validated via in vitro and in vivo experiments. The succinylation post-translation modifications (PTMs) pathway and the modified protein malate dehydrogenase 2 (MDH2), associated with STING-mediated reversal of cisplatin resistance, were screened using modification omics analysis. Site-specific mutants were constructed to investigate critical succinylation sites of MDH2. The desuccinylase of MDH2 was identified through co-IP/MS, and the molecular mechanism by which STING regulates the desuccinylase to inhibit MDH2 succinylation was elucidated. Succinylation-mimetic and desuccinylation mutants were generated to explore the role of MDH2 desuccinylation in mitochondrial respiration. Finally, the mechanism by which MDH2 desuccinylation reverses cisplatin resistance in NSCLC was clarified through in vitro and in vivo experiments.

Results: This study demonstrated that STING stabilizes the mitochondrial desuccinylase Sirtuin 5 (SIRT5) by reducing TRIM21-SIRT5 interaction, enhancing its ability to promote desuccinylation of MDH2 at lysine 314. This PTMs impairs MDH2 enzymatic function, leading to mitochondrial respiratory dysfunction, excessive mitochondrial DNA (mtDNA) damage, and activation of the cGAS-STING signaling pathway, ultimately restoring cisplatin sensitivity in resistant NSCLC cells.

Conclusion: This study uncovers a previously unrecognized STING/MDH2 desuccinylation feedback loop that integrates metabolic reprogramming with immune activation. The findings provide insights into the underlying mechanisms and identify STING and Succ-MDH2 (Lys 314) as potential therapeutic targets for developing effective strategies against cisplatin-resistant NSCLC.

Keywords: Cisplatin resistance; MDH2 desuccinylation; Mitochondrial dysfunction; Non-small cell lung cancer; STING; cGAS-STING signaling.