Resveratrol targeting MDM2/P53/PUMA axis to inhibit colonocyte apoptosis in DSS-induced ulcerative colitis mice

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by colon inflammation and ulceration, leading to increased intestinal permeability due to excessive apoptosis of colonocytes. This study evaluates the therapeutic potential of Resveratrol in UC. UC was induced in mice using dextran sulfate sodium (DSS), and colonic damage was assessed through colonic length, histology, and immunofluorescence. Single-cell sequencing was employed to investigate changes in the immune microenvironment after Resveratrol treatment. In vitro, the apoptosis of colonocytes were analyzed via measurements by DNA fragmentation, mitochondrial membrane potential, and annexin V/propidium iodide staining. The results showed that Resveratrol treatment significantly improved colonic damage in the UC model by reducing inflammation and mucosal injury. Single-cell sequencing indicated that Resveratrol mainly targeted colonocytes, decreasing apoptosis-related genes and the P53 pathway. In vitro, Resveratrol reduced DNA fragmentation, apoptotic cells, and improved mitochondrial function. Moreover, Resveratrol increased MDM2 expression, inhibiting P53-mediated apoptosis. Nutlin-3a, an MDM2 inhibitor, reversed these effects. MDM2 overexpression in the colon protected against DSS-induced damage. In conclusion, Resveratrol alleviates DSS-induced UC by inhibiting excessive apoptosis in colonocytes via the MDM2/P53/PUMA axis, positioning MDM2 as a potential therapeutic target for UC.