Nobiletin Regulates Gut Microbiota and Mediates HIF-1α to Alleviate DSS-Induced Ulcerative Colitis by Inhibiting Ferroptosis

While nobiletin (NOB), a polymethoxy flavonoid, shows therapeutic potential for various disorders, its efficacy in ulcerative colitis (UC) management remains unexplored. This study aims to elucidate novel molecular targets of NOB and decipher its mechanistic underpinnings in UC treatment. Through complementary cellular models and dextran sulfate sodium (DSS) induced UC in mice models, we systematically revealed that NOB ameliorates UC symptoms through ferroptosis suppression. Comprehensive analyses identified HIF-1α as a principal target interacting with NOB. Notably, 16S rRNA sequencing demonstrated NOB's remarkable capacity to remodel gut microbiota (GM) composition, characterized by enrichment of beneficial microbial taxa and depletion of pathogenic species. Collectively, our findings reveal that NOB exerts therapeutic effects against UC through dual mechanisms: HIF-1α-mediated ferroptosis inhibition and GM modulation synergistically restore colonic mucosal barrier integrity. This study provides the first evidence positioning NOB as a promising multitarget therapeutic agent for UC management.