Dual mechanisms of morin in bioavailability potentiation and hepatoprotection: Enhancing enrofloxacin safety in poultry through ABC transporter inhibition and antioxidant pathway activation.

Antimicrobial resistance (AMR) poses a major global public health threat. The low oral bioavailability of antibiotics in poultry, mediated by ATP-binding cassette (ABC) transporters, predisposes the host to subinhibitory conditions that exacerbate AMR transmission. However, earlier-generation ABC transporter inhibitors, such as verapamil and cyclosporine A, are limited by inherent hepatotoxicity. This study aimed to elucidate whether morin enhances the bioavailability of substrate drugs by inhibiting avian ABC transporters and to evaluate its potential in mitigating drug-induced liver injury (DILI). Using chicken embryo primary hepatocytes and chicken models, we investigated the inhibitory effects of morin on ABC transporter function and expression, and its impact on enrofloxacin oral bioavailability, through fluorescent substrate accumulation assays, molecular docking, and chicken xenobiotic receptor (CXR) reporter gene assays. Concurrently, employing an enrofloxacin and LPS co-induced liver injury model combined with oxidative stress markers, inflammatory cytokine detection, and histological analysis, we assessed the hepatoprotective effects of morin against DILI. Morin (60 mg/kg) significantly increased the oral bioavailability of enrofloxacin from 62.16% to 91.04% by directly inhibiting ABC transporter function and downregulating CXR-mediated transporter expression. Furthermore, morin effectively alleviated enrofloxacin-LPS-induced DILI through activation of the Nrf2-mediated antioxidant pathway and suppression of the NF-κB-mediated inflammatory response. In conclusion, morin functions as a novel dual-functional oral enhancer that not only boosts enrofloxacin bioavailability by inhibiting ABC transporters and downregulating their CXR-mediated expression but also confers hepatoprotection via the Nrf2/NF-κB pathways, thereby presenting a viable strategy to combat the AMR while ensuring drug safety in poultry production.