Exocarpium Citri Grandis Attenuates Lipopolysaccharide‐Induced Acute Liver Injury Through Suppression of Inflammatory, Apoptotic, Oxidative, and Ferroptotic Pathways

This study aimed to elucidate the therapeutic mechanisms of Exocarpium Citri Grandis (ECG) against lipopolysaccharide (LPS)-induced acute liver injury (ALI) using an integrated approach combining network pharmacology and experimental validation. The chemical profile of ECG was characterized via UHPLC-Q-Exactive MS. Male C57BL/6J mice were employed to establish an LPS-induced ALI murine model for evaluating hepatoprotective effects of ECG. Serum AST/ALT levels, histopathology changes, and inflammatory, apoptotic, oxidative, and ferroptotic markers were analyzed. Additionally, network pharmacology was used to identify the targets and pathways of ECG, while molecular docking validated interactions between bioactive compounds and key regulatory molecules. ECG treatment significantly reduced serum AST/ALT levels (<i>p</i> < 0.05-0.001) and alleviated hepatic inflammation and necrosis. Moreover, qPCR and Western blotting revealed that ECG markedly downregulated pro-inflammatory cytokines (IL-6, IL-1β, TNFα), inhibited cellular inflammation by downregulating the expression of proteins related to the TLR4/MyD88 pathway, counteracted oxidative stress by increasing Nrf2 nuclear translocation and the expression of genes such as NQO1, GCLC, and GCLM, suppressed apoptosis via modulation of Bax/Bcl2/CASP3, and inhibited ferroptosis by normalizing iron content and GPX4/SLC7A11 expression. Network pharmacology identified 127 shared targets between ECG and sepsis, highlighting critical pathways including TNF, p53, and IL-17 signaling. Molecular docking confirmed strong binding affinities (e.g., naringin with TP53: -13.23 kcal/mol) between ECG-derived flavonoids and coumarins with apoptosis and inflammation regulators. ECG mitigates LPS-induced ALI through coordinated anti-inflammatory, anti-apoptotic, anti-oxidative, and anti-ferroptotic mechanisms, mediated via multi-target modulation of critical pathways. These findings underscore the potential of ECG as a natural therapeutic candidate for ALI, thus warranting further clinical exploration.