Molecular Mechanism of TMEM126A Modulating PANoptosis and Proliferation via TRAF6/NF-κB Signalling Pathway in Non-Small Cell Lung Cancer

The mitochondrial transmembrane protein-126A (TMEM126A) is crucial for the accurate assembly of mitochondrial complex I and plays a significant role in preserving mitochondrial function. We aimed to investigate the expression of TMEM126A in non-small cell lung cancer (NSCLC), its biological impact on the malignant progression of NSCLC, and its underlying molecular mechanisms. Here we show TMEM126A was underexpressed in NSCLC and was closely correlated with clinicopathological factors and poor prognosis. In vitro and in vivo functional experiments validated the vital tumour-suppressing roles of TMEM126A in inhibiting cell proliferation and promoting PANoptosis and autophagy. Mechanistically, TMEM126A was identified to interact with and facilitate the autophagy-mediated degradation of TRAF6 via its own transmembrane domain, thereby suppressing the NF-κB signalling pathway and weakening the proliferation of NSCLC. In conclusion, TMEM126A plays a significant inhibitory role in NSCLC malignant progression, which provides experimental evidence to support the development of small-molecule inhibitors.