RPL27 promotes gastric cancer progression by enhancing oxidative phosphorylation via FMC1

Gastric cancer remains one of the leading causes of cancer-related mortality worldwide, highlighting the urgent need for novel biomarkers and therapeutic targets. Ribosomal proteins have emerged as critical regulators of tumorigenesis beyond their canonical roles in protein synthesis. In this study, we investigated the expression, functional role, and underlying mechanism of RPL27 in gastric cancer. RPL27 was significantly upregulated in gastric cancer tissues compared with adjacent normal tissues, as demonstrated by Western blot and immunohistochemistry. High RPL27 expression correlated with poor overall survival and showed potential as a prognostic biomarker. Functional assays revealed that RPL27 knockdown significantly suppressed gastric cancer cell proliferation, migration, and invasion. Transcriptomic analysis identified FMC1 as a key RPL27-downstream molecule, to regulate mitochondrial function, including membrane potential, morphology, DNA copy number, and ATP5A expression. Rescue experiments demonstrated that knockdown of FMC1 or treatment with the OXPHOS inhibitor oligomycin A partially reversed the malignant phenotypes induced by RPL27 overexpression. Furthermore, RPL27 knockdown significantly inhibited tumor growth in a xenograft mouse model. Collectively, our findings establish RPL27 as a novel oncogenic driver in gastric cancer and reveal that RPL27 promotes tumor progression through FMC1-dependent oxidative phosphorylation, suggesting that the RPL27-FMC1-mitochondrial function axis may represent a promising vulnerability for further investigation in gastric cancer.