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. The gene discussed is AKT1; the disease is head and neck squamous cell carcinoma.