Succinate Dehydrogenase in Lung Cancer: from Molecular Mechanisms to Clinical Implications

Lung cancer remains the malignancy with the highest global incidence and mortality rates, and its five-year survival rate is still unsatisfactory. Traditional treatment approaches face severe challenges from tumor heterogeneity and therapeutic resistance. Succinate dehydrogenase (SDH) is a key metabolic enzyme within mitochondria that participates in both the tricarboxylic acid (TCA) cycle and the electron transport chain. Through its unique tetrameric structure, it catalyzes the oxidation of succinate to fumarate and transfers electrons to ubiquinone, playing a central role in cellular energy metabolism. Recent studies indicate that SDH dysfunction can stabilize hypoxia-inducible factor-1α (HIF-1α) via the pseudohypoxia pathway, thereby inducing metabolic reprogramming, which is a mechanism implicated in the pathogenesis and progression of various cancers. This review systematically summarizes the molecular structural features and biological functions of SDH, along with its mechanisms of action in lung cancer initiation, progression, metastasis, and therapy resistance. Furthermore, it analyzes recent advances in potential diagnostic biomarkers and therapeutic targets based on SDH-mediated metabolic characteristics, with emphasis on the dual role of SDH5 in suppressing epithelial-mesenchymal transition (EMT) and promoting radiotherapy resistance, aiming to provide a theoretical foundation for a deeper understanding of lung cancer metabolism and the development of novel therapeutic strategies.