<i>Exocarpium Citri Grandis</i> Ameliorates Metabolic Disorders by Inhibiting Inflammatory Responses and NLRP3 Inflammasome Activation

<i>Exocarpium Citri Grandis</i> (ECG, known as <i>Huajuhong</i> in Chinese), as the fruit that can be used both as medicine and food, has gained attention for its hypolipidemic and anti-obesity effects. However, its lipid-lowering potential and ability to alleviate metabolic syndrome (MS) remain unexplored. This study aimed to confirm the therapeutic effects of ECG on postmenopausal MS and investigate its underlying mechanisms. An animal model of female postmenopausal MS was established using 8-week-old ovariectomized (OVX) mice. Starting from the third week after model establishment, the mice were orally administered at the doses of 25, 50, and 100 mg/kg for 12 consecutive weeks. HepG2 cells co-induced by oleic acid and palmitic acid (OA&PA) were used as an in vitro model. Ultra-high-performance liquid chromatography-Q-Exactive (UHPLC-Q-Exactive) analysis, histological examination, immunofluorescence, network pharmacology, molecular docking, molecular dynamics simulations, and other methods were employed for further analysis. ECG contains ingredients such as naringin and narirutin. In vitro experiments showed that ECG intervention significantly reduced reactive oxygen species (ROS) accumulation and downregulated the mRNA expression of <i>Srebp1, G6, Fas, Pgc1α, Acc, Casp1, Nfkb, IL1β, IL6, Txnip, Nlrp3</i>, and <i>ASC</i>. Additionally, ECG inhibited the protein expression of NF-κB, Txnip, NLRP3, ASC, and Caspase-1, while enhancing the expression of Trx-1. In vivo, ECG alleviated metabolic disorders in OVX mice by reducing lipid accumulation, attenuating inflammatory responses, and inhibiting NLRP3 inflammasome activation. Network pharmacology analysis and molecular dynamics identified the PI3K/AKT1 signaling pathway as a crucial target mediating the functional effects of ECG. ECG exerts therapeutic benefits in ameliorating postmenopausal MS-related metabolic disorders by inhibiting inflammatory responses, suppressing NLRP3 inflammasome activation, and modulating the PI3K/AKT1 signaling pathway, providing new insights into the application of ECG for managing postmenopausal MS.