Mitochondrially Encoded Cytochrome C Oxidase 1, a Hypoxia‐ and Lactylation‐Related Gene, Acts as a Tumor Suppressor and Therapeutic Target in Oral Squamous Cell Carcinoma

Background Aberrant expression of mitochondrially encoded Cytochrome c Oxidase Subunit 1 (MT‐CO1) has increasingly been associated with tumor invasiveness and adverse clinical outcomes across multiple malignancies. However, its functional role and regulatory mechanisms in oral squamous cell carcinoma (OSCC) remain poorly understood. Methods Transcriptomic data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) were integrated to identify genes consistently dysregulated across datasets. Candidate prognostic genes were subsequently prioritized using Cox proportional hazards regression in combination with least absolute shrinkage and selection operator (LASSO) regression. A multi‐omics validation framework was then applied, encompassing analysis of MT‐CO1 expression in OSCC, protein‐level validation using the Human Protein Atlas, and evaluation of associations with clinicopathological characteristics. The functional effects of MT‐CO1 were evaluated in OSCC cell lines using gain‐of‐function assays. To assess the feasibility of pharmacologically targeting MT‐CO1, molecular docking and subsequent molecular dynamics simulations were performed to characterize the interaction between amorolfine and MT‐CO1; mechanistic rescue experiments were then conducted to determine whether the drug's effects were MT‐CO1‐dependent. Results MT‐CO1 was associated with hypoxia and lactylation and was downregulated in OSCC, with lower expression correlating with poorer survival. MT‐CO1 overexpression reduced cell viability, proliferation, and invasion while enhancing apoptotic signaling in vitro. Computational analyses further predicted a stable, high‐affinity interaction between amorolfine and MT‐CO1. Importantly, MT‐CO1 suppression attenuated the antineoplastic effects of amorolfine in OSCC cells, supporting an MT‐CO1‐dependent mechanism of action. Conclusions MT‐CO1 as an underappreciated tumor‐suppressive factor in OSCC and support further evaluation of amorolfine for therapeutic repurposing. MT‐CO1 may serve as a biomarker of treatment response and that the MT‐CO1–amorolfine axis may represent an actionable therapeutic vulnerability in OSCC.