Abstract 5423: A focused shRNA library screening identifies MRPL38 as an oncogenic regulator of lung cancer via regulation of mitochondrial homeostasis

To identify a novel gene that contributes to lung cancer progression, we performed RNA interference genetic screening combined with multi-omics analysis of never-smoker lung cancer cohort (GSE256091). As a result of the screening and MAGeCK analysis, mitochondrial ribosomal protein L38 (MRPL38) was identified as a positive regulator of lung cancer progression. Mitochondrial dysfunction and metabolic reprogramming are key features of lung cancer. Despite their significance, the precise underlying mechanisms of these processes and the role of MRPL38 in lung cancer progression have not been fully elucidated. A significant upregulation of MRPL38 was observed in lung cancer patient tissues, which was associated with advanced tumor stages and poor prognosis. Knockdown of MRPL38 significantly reduced cell viability and colony formation and increased apoptosis in human lung cancer cells. Moreover, MRPL38 has been found to be crucial for maintaining mitochondrial protein translation and homeostasis. Loss-of-function experiments targeting MRPL38 in various lung cancer cell lines resulted in alterations in oxidative phosphorylation (OXPHOS) complex proteins, oxygen consumption rate (OCR), and mitochondrial biogenesis. In MRPL38-deficient cells, the expression levels of proteins encoding subunits of the respiratory chain complexes were significantly reduced, and both basal and maximal mitochondrial respiration were decreased. Furthermore, the inhibition of MRPL38 was found to significantly reduce the mass and number of mitochondria associated with mitochondrial biogenesis. These results suggest that MRPL38, a novel regulator in lung cancer, may promote lung cancer progression by regulating mitochondrial homeostasis. Citation Format: Jieun Seo, So Young Lee, Sangwon Byun, Kyung Chan Park. A focused shRNA library screening identifies MRPL38 as an oncogenic regulator of lung cancer via regulation of mitochondrial homeostasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5423.