Sitagliptin ameliorates radiation-induced oral mucositis by inhibiting oxidative damage and inflammatory response via TLR2/MyD88/NF-κB signaling pathway.

Radiotherapy for head and neck cancers is frequently complicated by radiation-induced oral mucositis (RIOM), which can compromise treatment tolerance and negatively affect patients' quality of life. Current preventive and therapeutic options remain limited, highlighting the need for safer and more effective interventions. The development of RIOM involves a cascade of radiation-triggered oxidative stress, epithelial injury, and sustained inflammatory responses. Given the reported antioxidant and anti-inflammatory activities of sitagliptin, a widely used dipeptidyl peptidase - 4 inhibitor, we investigated its potential protective effects against RIOM. Here we show that oral sitagliptin markedly reduces mucosal ulceration and radiation-associated weight loss in mouse models of localized head-and-neck irradiation, while preserving mucosal thickness and basal epithelial stem cells and sustaining proliferative activity after irradiation. Sitagliptin limits reactive oxygen species accumulation and lipid peroxidation, restores glutathione levels and superoxide dismutase activity, and reduces DNA damage, apoptosis, inflammatory cytokine expression, and inflammatory-cell infiltration. Mechanistically, sitagliptin inhibits TLR2/MyD88/NF-κB signaling, whereas pharmacological activation of TLR2 partially reverses its protective effects in vitro, providing further evidence that this pathway contributes to sitagliptin-mediated protection. Sitagliptin is well tolerated in healthy mice, causes no detectable hypoglycemia or organ toxicity, and does not measurably impair radiotherapy-mediated tumor control or tumor radiosensitivity. Collectively, these results demonstrate that sitagliptin protects against RIOM through coordinated antioxidant, anti-apoptotic, and anti-inflammatory actions involving suppression of TLR2/MyD88/NF-κB signaling, while maintaining tumor radiosensitivity. Its established clinical use and the efficacy and tolerability observed in our preclinical models support further evaluation of sitagliptin for RIOM.