Lipid homeostasis dysregulation in oral cancer drives metabolic reprogramming and offers novel diagnostic and therapeutic opportunities.

Oral cancer remains a significant global health challenge, with oral squamous cell carcinoma (OSCC) being the predominant histological type. Recent research has highlighted the critical role of metabolic reprogramming in oral carcinogenesis, particularly alterations in lipid homeostasis that contribute to disease progression and development. This review synthesizes current knowledge on lipid metabolism dysregulation in oral cancer, focusing on key aspects of metabolic reprogramming mechanisms, serum lipid profile alterations, lipid peroxidation pathways, immunometabolic interactions, and emerging therapeutic strategies. Mechanistically, OSCC exhibits significant alterations in key lipid metabolic enzymes, including upregulation of fatty acid synthase and ATP citrate lyase, and downregulation of carboxylesterase 2 (CES2), collectively promoting tumor growth and metastasis. These enzymatic changes are orchestrated through complex signaling pathways, notably the PI3K/AKT/mTOR axis, and manifest in altered membrane lipid composition, particularly within lipid microdomains that influence both cell signaling and drug resistance. Clinically, OSCC patients demonstrate characteristic serum lipid profile alterations, including reduced levels of total cholesterol, high-density lipoprotein cholesterol, and specific apolipoproteins, which show promise as non-invasive biomarkers for early detection and prognosis. Furthermore, enhanced lipid peroxidation through reactive oxygen species presents a double-edged sword in carcinogenesis, with oxidation products like malondialdehyde both contributing to mutagenesis and serving as potential diagnostic indicators. The complex interplay between lipid metabolism and tumor immunity, particularly through CD36 and sphingosine-1-phosphate signaling pathways, creates opportunities for immunometabolic interventions. Emerging therapeutic strategies targeting lipid metabolism include lipid-based nanoparticle drug delivery systems, metabolic enzyme inhibitors, and immunometabolic modulators, with promising preclinical results. Despite significant advances, challenges remain in translating these findings into clinical applications, necessitating further research on combination therapies, biomarker validation, and personalized treatment approaches. This comprehensive review provides valuable insights for both basic researchers and clinicians, potentially facilitating the development of novel diagnostic tools and therapeutic strategies for oral cancer management.