Montelukast attenuates intestinal mucositis induced by 5-fluorouracil via upregulation of HO-1 and PPAR-γ and suppression of TLR4/NF-κB/HMGB1 and caspase-3 pathways.

5-Fluorouracil (5-FU) is a commonly employed chemotherapeutic drug, but its clinical utility is limited by intestinal toxicity. Montelukast (MTK), a CysLTR1 antagonist, is known for its antioxidative and anti-inflammatory actions. However, its protective potential against 5-FU-induced intestinal injury remains inadequately defined. This investigation assessed whether MTK could mitigate 5-FU-induced intestinal mucositis and explored the signals involved. Rats were divided into four groups: control, MTK (10 mg/kg/day, orally), 5-FU (100 mg/kg/day, intraperitoneally), and MTK + 5-FU. Administration of 5-FU produced pronounced intestinal mucosal injury, including villus shortening, crypt destruction, goblet cell loss, and heightened inflammatory infiltration. These pathological changes were associated with suppression of the PPAR-γ and HO-1 antioxidant enzyme, activation of TLR4/NF-κB/HMGB1 signaling, and cleaved caspase-3 activity. MTK treatment significantly ameliorated histopathological alterations, restored mucosal architecture, enhanced HO-1 and PPAR-γ expression, suppressed TLR4/NF-κB/HMGB1 activation, and attenuated apoptosis. In conclusion, MTK protects against 5-FU-induced mucositis, serving as a promising adjunctive treatment for chemotherapy-induced toxicity.