Abstract
BACKGROUND/PURPOSE: Head and neck squamous cell carcinoma (HNSCC), including oral squamous cell carcinoma (OSCC), remains a major malignancy with limited therapeutic efficacy. Apoptosis-inducing factor mitochondria-associated 2 (AIFM2), also known as ferroptosis suppressor protein 1, regulates ferroptosis and tumor progression. This study investigated the oncogenic function, clinical relevance, and regulation of AIFM2 in OSCC. MATERIALS AND METHODS: Transcriptomic data from TCGA HNSCC and in-house OSCC RNA-Seq datasets were analyzed to assess AIFM2 expression and its association with clinicopathological features and outcomes. Functional assays evaluated the effects of AIFM2 knockdown or overexpression on OSCC cell proliferation, migration, invasion, and therapeutic response. MicroRNAs targeting AIFM2 were identified through bioinformatics, luciferase reporter, and mimic assays. A Light Gradient Boosting Machine (LGBM) model was used for prognostic prediction. RESULTS: AIFM2 overexpression was associated with advanced stage, poor tumor differentiation, and unfavorable survival in HNSCC/OSCC. AIFM2 knockdown suppressed, whereas its overexpression enhanced, OSCC cell proliferation, migration, and invasion, while exerting minimal effects on cisplatin, palbociclib, or cold atmospheric plasma sensitivity. miR-32-5p and miR-432-5p directly targeted AIFM2 and were downregulated in tumors. AIFM2-associated transcripts were enriched in pathways related to oxidative stress, lipid metabolism, and E2F targets. The LGBM-derived AIFM2 gene signature demonstrated strong prognostic predictive power. CONCLUSION: AIFM2 acts as an oncogenic driver in OSCC, regulated by tumor-suppressive miR-32-5p and miR-432-5p, and serves as a potential prognostic biomarker and therapeutic target.