RPL27 Promotes Gastric Cancer Progression by Enhancing Oxidative Phosphorylation Via FMC1

Gastric cancer remains a leading cause of cancer‐related mortality worldwide, underscoring the urgent need for novel biomarkers and therapeutic targets. Ribosomal proteins have recently emerged as critical regulators of tumorigenesis beyond their classical roles in protein synthesis. Here, we investigated the expression, functional significance, and underlying mechanism of RPL27 in gastric cancer. RPL27 was markedly upregulated in gastric cancer tissues compared with adjacent normal tissues, as demonstrated by Western blotting and immunohistochemistry. High RPL27 expression was significantly associated with poor overall survival, suggesting its potential as a prognostic biomarker. Functional assays revealed that RPL27 knockdown substantially suppressed gastric cancer cell proliferation, migration, and invasion. Transcriptomic analysis identified FMC1 as a key downstream molecule of RPL27, mediating its regulatory effects on mitochondrial function, including alterations in membrane potential, morphology, DNA copy number, and ATP5A expression. Rescue experiments demonstrated that either FMC1 knockdown 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, these findings establish RPL27 as a novel oncogenic driver in gastric cancer and demonstrate that it promotes tumor progression through FMC1‐dependent regulation of oxidative phosphorylation. The RPL27‐FMC1‐mitochondrial function axis may thus represent a promising vulnerability for therapeutic intervention in gastric cancer.