Targeting ferroptosis by trimetazidine and probiotics to attenuate 5-fluorouracil-induced intestinal mucositis in mice

Intestinal mucositis is a common side effect in cancer patients receiving chemotherapy, yet effective treatment options are lacking. This study aimed to investigate the potential protective effects of trimetazidine and probiotics combination in a 5-FU-induced intestinal mucositis model. We hypothesized that these agents would attenuate mucositis through anti-inflammatory and antioxidant effects associated with modulation of ferroptosis-related pathways, particularly through Nrf2-associated regulatory mechanisms. 5-fluorouracil in a dose of 50 mg/kg/day i.p. for 6 consecutive days starting from the 11th to the 16th day for induction of chemotherapy-induced intestinal mucositis (CIM) and mice were divided into five equal groups as follows: control group, untreated group, trimetazidine group, probiotics group, and trimetazidine + probiotics group. The effects of these drugs on inflammation, oxidative stress, and ferroptosis were assessed. Treatment with trimetazidine and probiotics in combination produced further improvement in disease activity, reflected by increased body weight and reduced diarrhea scores. Significant reductions were observed in IL-1β and MDA levels, with parallel increases in SOD, GPx4, CAT, Nrf2, and SLC7A11. The combination also provided additional improvement in intestinal structure (villus height, crypt depth, and enteritis score) compared with each monotherapy group. Either trimetazidine or probiotics alleviated 5-FU-induced intestinal mucositis and might be considered promising candidates for preventing CIM by anti-inflammatory, antioxidant, and mechanisms associated with modulation of ferroptosis-related pathways.