Fraxinellone suppresses inflammatory bowel disease by targeting PINK1 and activating PINK1/Parkin-mediated mitophagy

The onset and progression of inflammatory bowel disease (IBD) are closely associated with mitochondrial dysfunction and oxidative stress, and an imbalance in PINK1/Parkin-mediated mitophagy is considered a key pathogenic mechanism; however, effective intervention strategies targeting this pathway are limited. Therefore, this study aims to investigate the protective effects of the natural bioactive compound Fraxinellone (FRA) against IBD and its underlying molecular mechanisms. In vivo experiments demonstrated that FRA significantly alleviated Dextran Sulfate Sodium (DSS)-induced colitis in mice, improving weight loss, colonic shortening and histopathological damage, whilst effectively reducing oxidative stress levels. In vitro model of LPS-mediated intestinal epithelial cell damage revealed that FRA significantly improved mitochondrial dysfunction, inhibited ROS accumulation, inflammatory responses and cell death, whilst restoring intestinal epithelial barrier function. Further studies using molecular docking and cell-based Cellular Thermal Shift Assay (CETSA) confirmed that FRA exerts its protective effects by directly binding to PINK1 and activating PINK1/Parkin-dependent mitophagy; conversely, its mitochondrial protective and anti-inflammatory effects were markedly attenuated following PINK1 knockdown. In summary, FRA exerts its anti-IBD effects by targeting PINK1 and activating PINK1/Parkin-dependent mitophagy, thereby improving mitochondrial homeostasis and alleviating oxidative stress and inflammatory damage. This study not only reveals a novel mechanism by which FRA regulates mitochondrial quality control to improve IBD, but also provides a new theoretical basis for precision therapeutic strategies targeting the PINK1/Parkin pathway, whilst offering a potential direction for the clinical translation of natural products in the prevention and treatment of IBD.