Poricoic acid a ameliorates ulcerative colitis via AMPK/PPARγ pathway-dependent cellular senescence inhibition and concomitant gut microbiota-metabolome modulation

BACKGROUND: Ulcerative colitis (UC) is an intractable inflammatory bowel disorder characterized by persistent intestinal inflammation and impaired gut barrier integrity. Its pathogenesis is multifactorial, involving gut microbiota dysbiosis, metabolic dysfunction, and cellular senescence. Current therapeutic regimens remain limited, underscoring an urgent need for innovative agents that target these interrelated pathological cascades. PURPOSE: This study aimed to evaluate the pharmacological effects of poricoic acid A (PAA) on DSS-induced senescence in intestinal epithelial cells and in a murine model of ulcerative colitis (UC), as well as the underlying molecular mechanisms. METHODS: We established a DSS-stimulated senescent intestinal epithelial cell model and a DSS-induced UC mouse model. Multi-omics and bioinformatics strategies, including network pharmacology, transcriptome profiling, gut metagenomics, and intestinal targeted metabolomics, were combined with molecular docking to predict candidate signaling axes. Subsequent pharmacological inhibition and siRNA-mediated silencing assays were performed to validate core pathways functionally. RESULTS: PAA robustly suppressed DSS-induced senescence and inflammatory responses in intestinal epithelial cells. In vivo assays verified that PAA alleviated UC-related manifestations, including body weight loss, rectal hemorrhage, and colonic histological injury. Joint network pharmacology and transcriptomic screening identified the AMPK/PPARγ as the core pathway mediating PAA's bioactivity. Mechanistic experiments confirmed that PAA directly bound and activated PPAR, further functionally triggering downstream AMPK/SirT1/PGC1α signaling. Blockade of AMPK via pharmaceutical antagonists or siRNA largely abolished PAA's anti-senescence and anti-inflammatory capacities; PPARγ suppression, in turn, secondary deactivated the AMPK and its downstream functional effectors. In mouse models, AMPK inhibition drastically compromised PAA's protective effects against UC. Moreover, PAA treatment of UC is closely associated with remodeling of the gut microbiome-metabolome axis and restoration of intestinal homeostasis. CONCLUSION: PAA exerts potent anti-senescence, anti-inflammatory, and colon-protective effects in UC via activating the AMPK/PPARγ signaling pathway. Such beneficial activity may be associated with the normalization of gut microbiota-metabolome homeostasis. This work identifies novel molecular targets and a promising lead compound for the intervention of ulcerative colitis.