BackgroundHead and neck squamous cell carcinoma (HNSCC) constitutes a major clinical challenge that severely affects patient survival. Mitochondrial ribosomal protein (MRP) family plays an important role in energy metabolism by participating in mitochondrial oxidative phosphorylation. However, their roles in HNSCC and the underlying mechanisms are still unclear.MethodsSingle-cell analysis highlighted MRPL21 as a notable biomarker of HNSCC. Human HNSCC tissues, cell lines, and xenograft models in nude mice were used to explore the expression and function of MRPL21. The mass spectrometry was performed to analyze the potential binding targets of MRPL21. In vitro and in vivo experiments were performed to evaluate the effect of MRPL21 on autophagy and cisplatin resistance. The inhibitory actions of siMRPL21 nanodelivery systems on HNSCC progression were also evaluated in vivo.ResultsClinically, relatively high expression level of MRPL21 was associated with poor prognosis in HNSCC patients, and overexpression of MRPL21 significantly promoted HNSCC tumorigenesis, metastasis, and cisplatin resistance. Mechanistically, MRPL21 upregulated mitochondrial oxidative phosphorylation (OXPHOS) and increased PARylation level, inhibited autophagy through activating the downstream PI3K/AKT/mTOR signaling pathway, and ultimately led to tumor progression and cisplatin resistance in HNSCC.ConclusionWe conclude that MRPL21 is a novel biomarker and therapeutic target of HNSCC progression and cisplatin resistant, which may provide a new approach for overcoming cisplatin resistance in HNSCC patients.