MRPL21 (mitochondrial ribosomal protein L21) is a structural component of the mitochondrial large ribosomal subunit essential for mitochondrial translation and oxidative phosphorylation (OXPHOS) 12. Beyond its canonical role in energy metabolism, MRPL21 has emerged as a critical oncogenic factor across multiple cancer types. Mechanistically, MRPL21 promotes cancer progression through several pathways. In head and neck squamous cell carcinoma (HNSCC), MRPL21 upregulates OXPHOS and increases PARylation levels, suppressing autophagy via the PI3K/AKT/mTOR signaling axis 1. In hepatocellular carcinoma (HCC), MRPL21 promotes proliferation by conferring apoptotic resistance through TP53 mutation-induced mechanisms, modulating mitochondrial membrane potential and reactive oxygen species generation 3. In neuroblastoma, MRPL21 knockdown impairs cell proliferation, migration, invasion, and mitochondrial OXPHOS 2. Clinically, MRPL21 is frequently overexpressed across cancers (HNSCC, HCC, lung adenocarcinoma, neuroblastoma, esophageal squamous cell carcinoma) and consistently associates with poor prognosis and treatment resistance 14536. High MRPL21 expression correlates with immunosuppressive tumor microenvironments and altered immune infiltration 25. MRPL21 shows promise as a diagnostic and prognostic biomarker and therapeutic target, particularly for overcoming cisplatin resistance in HNSCC and predicting outcomes in lung adenocarcinoma 15.