Metformin ameliorates 5-fluorouracil-induced intestinal injury by inhibiting cellular senescence, inflammation, and oxidative stress

5-Fluorouracil (5-Fu), which inhibits metabolism, is an essential part of the first-line treatment of colorectal cancer but causes severe side effects, including nausea, vomiting, anorexia, and gastrointestinal injury with severe diarrhea, and requires dose reduction or treatment deferral, resulting in a poor prognosis. Metformin has anti-inflammatory effects, but its role in the mechanism of treatment in intestinal injury caused by 5-Fu remains unclear. In our present research, we assessed the impact of metformin on damage to the intestine from 5-Fu by inhibiting cellular senescence, intestinal canal inflammation, and oxidative stress by using HUVECs, HIECs, and male BALB/c mice. It has been found that intestinal damage caused by 5-Fu is associated with the accumulation of senescent cells. Metformin relieved intestinal damage by suppressing the activity of senescence-beta-galactosidase (SA-beta-gal) and the development of the senescence-associated secretory phenotype (SASP). Furthermore, we observed that the anti-aging effect was closely correlated with mTOR suppression in cell and mouse models. In conclusion, this is the first time that metformin has been able to reduce intestinal damage related to chemo-therapy by inhibiting cellular senescence and oxidative stress.