Targeting the lactate receptor GPR81 suppresses tumor progression by disrupting glycolytic metabolism in oral squamous cell carcinoma

OBJECTIVES: Cancer cells reprogram glucose metabolism toward aerobic glycolysis, a phenomenon known as the Warburg effect. This metabolic shift results in substantial lactate accumulation within the tumor microenvironment. Although lactate has been implicated in tumor aggressiveness, the underlying mechanisms remain poorly understood. Recent studies have identified lactate as an active signaling molecule that exerts its effects through G-protein-coupled receptor 81 (GPR81). The present study aimed to elucidate the clinical and functional significance of GPR81 in the progression of oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: GPR81 expression was evaluated using human OSCC tissue specimens (n = 84). In vitro functional assays and xenograft studies were performed using GPR81-knockdown HSC-3 and SAS cell lines. The role of GPR81 in oral carcinogenesis was further examined using an immunocompetent 4-nitroquinoline 1-oxide (4-NQO)-induced carcinogenesis model in Gpr81 knockout mice. RESULTS: GPR81 expression was significantly higher in OSCC specimens than in normal oral mucosa. GPR81 knockdown suppressed cell proliferation and tumor formation in OSCC models. In the 4-NQO-induced carcinogenesis model, the area of squamous cell carcinoma within the tongue was significantly reduced in Gpr81 knockout mice compared with wild-type controls. Mechanistically, GPR81 knockdown reduced ATP production and was associated with decreased expression of glycolytic genes including PFKL, PKM2 and LDHA. CONCLUSION: Through a multi-model approach, we identify GPR81 as an important regulator of oral carcinogenesis via glycolytic reprogramming. These findings suggest that targeting the lactate-GPR81 signaling axis may represent a promising therapeutic strategy for aggressive OSCC.