Transmembrane protein 106C promotes lung adenocarcinoma progression through GSPT1-mediated compensatory mitophagy

Despite advances in lung adenocarcinoma (LUAD) therapy, 5-year survival remains low, necessitating new targets. In this study, TMEM106C and GSPT1 expressions were evaluated using qRT-PCR and Western blot. The targeting relationship between TMEM106C and GSPT1 was validated by RNA-sequencing, RNA immunoprecipitation, and cycloheximide tracing assays. Functional effects of cells were assessed through CCK-8, colony formation, flow cytometry, wound healing, and Transwell. Western blot was used to study the expression of autophagy-related markers. The changes in mitophagy after transfection or treatment were observed by GFP-mRFP-LC3 fluorescence, transmission electron microscopy, and mitochondria-specific markers. In vivo effects were verified in nude mouse models. The results showed that TMEM106C was significantly upregulated in TCGA-LUAD dataset, clinical samples, and LUAD cells, correlating with poor prognosis. Silencing TMEM106C suppressed the growth and metastatic potential of A549 and H1299 cells while increasing apoptotic cell death. Similarly, TMEM106C knockdown suppressed xenograft tumor growth and tumor weight, whereas overexpression had the opposite effect. GSPT1 is a downstream gene of TMEM106C, and its overexpression reversed the inhibitory function of TMEM106C silencing on lung cancer growth, migration, and invasion-associated phenotypes. Moreover, GSPT1 promoted Parkin ubiquitination and was associated with altered Parkin turnover under mitochondrial stress, accompanied by enhanced compensatory mitophagy. In H1299 cells, TMEM106C silencing impaired compensatory mitophagy and increased apoptosis, whereas restoration of GSPT1 partially rescued the tumor-suppressive effects of TMEM106C silencing. In summary, TMEM106C promotes LUAD progression by maintaining GSPT1 expression and enhancing compensatory mitophagy, accompanied by altered Parkin ubiquitination and reduced apoptosis.