Lometrexol targets MRPL2 to suppress NSCLC via dual regulation of mitochondrial ribosomal activity and nuclear PDCD11/ Ca2+ signaling

Non-small cell lung Cancer (NSCLC) remains a leading cause of cancer-related mortality, necessitating novel therapeutic targets. Recent studies emphasize the significance of mitochondrial ribosomal proteins (MRPs) in Cancer, showing altered expression in different cancers and their potential as prognostic biomarkers and therapeutic targets. We identified that MRPL2 was upregulated in NSCLC and decreased expression of MRPL2 diminished tumorigenicity of NSCLC. Mechanistically, USP21 directly interacts with and stabilized MRPL2 via deubiquitination process through its USP domain. Moreover, The upregulation of MRPL2 influenced mitochondrial function via its localization to mitochondria, facilitating its role in ribosomal activity. Additionally, our findings indicated that MRPL2 can also enhance the intracellular calcium signaling pathway through its nuclear localization and interaction with PDCD11, thereby playing a regulatory role in the progression of NSCLC. Furthermore, we identified lometrexol as a potential MRPL2 inhibitor that can hinder NSCLC development. Taken together, we identify a MRPL2-regulated ribosomal and non-ribosomal mechanism that involves the USP21/MRPL2/PDCD11/CA²⁺ axis in NSCLC tumorigenesis, which could serve as a potential target for the treatment of NSCLC.

MRPL2; Non-small-cell lung cancer; USP21; Ubiquitylation.