Hepatoprotective capacity of Zanthoxylum bungeanum pericarp in acetaminophen-evoked hepatic injury: Convergent evidence from redox imbalance, inflammasome, endoplasmic reticulum stress, and metabolomic reprofiling

Zanthoxylum bungeanum Maxim. pericarp is extensively applied as an edible spice and possesses prominent pharmacological merits, yet the systematic molecular mechanisms underlying its protective action against drug-induced liver damage have not been comprehensively clarified. This study integrated in vivo and in vitro pharmacology, untargeted metabolomics, phytochemical profiling, and computational modeling to elucidate the protective effects and mechanisms of ZB against APAP-evoked hepatic injury. Male KM mice received ZB (225 or 450 mg/kg) or ammonium glycyrrhizinate (AG; 200 mg/kg) for 14 consecutive days, followed by a single APAP challenge (300 mg/kg). High-dose ZB raised 24 h survival from 60% to 85%, reduced circulating aminotransferases and lactate dehydrogenase, and ameliorated hepatic necrosis. Mechanistically, ZB re-established antioxidant balance (SOD, GSH, MDA), downregulated NLRP3 inflammasome signaling (NLRP3, cleaved caspase-1, mature IL-1β), and alleviated endoplasmic reticulum (ER) stress responses (GRP78, p-PERK, and CHOP) while partially restoring MANF. Untargeted metabolomics revealed partial normalization of phenylalanine, tyrosine, pyrimidine, and arginine-proline metabolism. Consistent protection was observed in APAP-treated AML12 hepatocytes. UPLC-Q-Orbitrap MS identified 44 constituents, among which luteolin 7-(6″- E -cinnamylglucoside) emerged—through molecular docking coupled with molecular dynamics simulations—as a putative PERK-interacting candidate. These findings establish that ZB pericarp confers hepatoprotection through coordinated oxidative stress, inflammatory signaling, and ER stress pathways, providing a research basis for future functional food-related applications.