Qilin Hu, Wenhan Liu, Xiangyu Chen, Shuyi Wang, Lutong Cai, Ruotong Liu, Tuan Wang, Zhaoqi Wu, Li Li, Lei Xue
Mitochondrial metabolic reprogramming is a hallmark of tumor progression, yet its gene-level determinants in oral squamous cell carcinoma (OSCC) remain poorly defined. Here, we integrated multi-omics analyses, machine learning, and experimental validation to elucidate the mitochondrial energy metabolism landscape in OSCC. A six-gene prognostic signature (CTSG, HPRT1, SLC20A1, TRIB3, MTFP1, and ADA) was constructed using Cox regression, CoxBoost, and random survival forest algorithms, which accurately predicted patient survival and delineated distinct immune microenvironment patterns in OSCC. Among these genes, HPRT1 emerged as a pivotal mitochondrial metabolic driver. Single-cell transcriptomics revealed that HPRT1 was predominantly expressed in malignant epithelial clusters and correlated with proliferative and immunosuppressive phenotypes. Validation in patient tissues and xenograft models confirmed that HPRT1 overexpression promoted tumor growth. Multiplex immunofluorescence on tissue microarrays demonstrated that high HPRT1 expression was associated with increased M2 macrophage infiltration and reduced densities of CD8⁺ T cells and M1 macrophages, indicating its role in establishing an immunosuppressive tumor microenvironment. Structure-based virtual screening, molecular dynamics simulations, and in vivo xenograft experiments identified troxerutin as a potential HPRT1-binding compound with favorable binding stability and free energy. Collectively, our study identifies HPRT1 as a key regulator linking mitochondrial metabolism and immune evasion in OSCC, providing a promising therapeutic target and supporting drug repurposing strategies for precision oncology.