Abstract Head and neck squamous cell carcinoma (HNSCC), including oral squamous cell carcinoma (OSCC), is a prevalent malignancy with limited therapeutic success. Apoptosis-inducing factor mitochondria-associated 2 (AIFM2), also known as ferroptosis suppressor protein 1, has been implicated in ferroptosis regulation and cancer progression, yet its role in HNSCC/OSCC remains unclear. This study investigated the oncogenic functions, clinical relevance, and epigenetic regulation of AIFM2 in OSCC. Transcriptomic data from TCGA-HNSCC and in-house OSCC RNA-Seq datasets were analyzed to assess AIFM2 expression and clinical associations. Functional assays examined the effects of AIFM2 knockdown and overexpression on OSCC cell proliferation, migration, invasion, and drug responses. Bioinformatic prediction, luciferase reporter, and miRNA mimic assays were performed to identify microRNAs regulating AIFM2. A Light Gradient Boosting Machine (LGBM) model was employed to predict patient mortality risk. High AIFM2 expression correlated with advanced stage, poor differentiation, p16 negativity, and worse survival in HNSCC/OSCC. AIFM2 knockdown reduced migration and invasion, while overexpression enhanced proliferation, migration, and invasion but had minimal impact on sensitivity to cisplatin, palbociclib, or cold atmospheric plasma. Bioinformatic and experimental analyses identified miR-32-5p and miR-432-5p as direct suppressors of AIFM2, both downregulated in tumors. AIFM2-associated transcripts were enriched in pathways related to oxidative stress, lipid metabolism, and E2F targets. Furthermore, the AIFM2-associated gene expression signature generated by the LGBM model effectively stratified patients by prognostic risk. Collectively, these findings indicate that AIFM2 functions as an oncogenic driver in OSCC, promoting tumor progression and poor prognosis, and is epigenetically regulated by tumor-suppressive miR-32-5p and miR-432-5p, representing a potential prognostic biomarker and therapeutic target. Citation Format: Chung-Hsien Chou, Shu-Chun Lin, Kuo-Wei Chang.. Apoptosis-inducing factor mitochondria-associated 2 (AIFM2) functions as an oncogenic driver and prognostic biomarker in oral squamous cell carcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3934.
Chou et al. (2026) studied this question.