Ethnopharmacological relevance: Penthorum chinense Pursh, a medicinal plant used in traditional Miao medicine, contains a variety of bioactive compounds and is well known for its significant hepatoprotective properties. Quercetin (QUE), one of the most widely investigated hepatoprotective flavonoids derived from P. chinense, has garnered considerable attention owing to its potent antioxidant and anti-inflammatory activities. Nevertheless, the precise molecular mechanisms through which QUE attenuates LPS-induced liver inflammation have not been fully elucidated.
Aim of the study: This study aimed to explore the protective effect of QUE against LPS-induced inflammatory liver injury and to clarify the underlying molecular mechanisms.
Materials and methods: A chicken model of liver inflammation was established via intraperitoneal injection of LPS (1.5 mg/kg). To assess the protective effects of QUE, the compound (10 mg/kg) was administered by oral gavage for six consecutive days prior to LPS challenge. Histopathological and ultrastructural changes in liver tissues were evaluated using hematoxylin and eosin (H&E) staining and transmission electron microscopy (TEM), respectively. Oxidative stress markers and antioxidant enzyme activities were also measured in liver tissues. Integrated network pharmacology and bioinformatics analyses were employed to identify core potential targets of QUE. Further validation experiments, including immunofluorescence co-localization, Western blotting, RT-qPCR, and in vitro cell culture assays, were conducted to elucidate the molecular mechanisms underlying QUE mediated attenuation of LPS induced liver inflammation.
Results: QUE effectively ameliorated LPS-induced inflammatory liver injury, as evidenced by a significant reduction in hepatic levels of the oxidative stress marker malondialdehyde (MDA) and a marked increase in the activities of key antioxidant enzymes, including superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), total antioxidant capacity (T-AOC), and catalase (CAT). Furthermore, QUE administration significantly downregulated the expression of pyroptosis-related proteins (NLRP3, GSDMD, ASC, and Caspase-1), restored the LPS-induced imbalance in macrophage M1/M2 polarization, and suppressed the expression of chemokines such as CCL4, CCL17, CCL19, and MIF. QUE treatment also significantly reduced the levels of pro-inflammatory cytokines (IL-18, IL-1β, TNF-α, and IL-6) while upregulating the anti-inflammatory cytokine IL-10. Moreover, QUE markedly inhibited the detrimental crosstalk between LPS-induced pyroptosis and M1 macrophage activation. Integrated network pharmacology and bioinformatics analyses predicted the core targets and pathways involved, and subsequent experimental validation confirmed that QUE attenuates hepatic inflammation primarily through inhibition of the ROS/NLRP3 signaling pathway.
Conclusions: This study demonstrates that QUE alleviates LPS-induced liver injury in chickens by suppressing the ROS/NLRP3 pathway, thereby interrupting the pathological crosstalk between pyroptosis and M1 macrophage polarization. These findings offer a promising therapeutic strategy rooted in traditional medicine for the treatment and prevention of inflammatory liver diseases.
Keywords: Chicken; Liver inflammation; M1 polarization; Oxidative stress; Pyroptosis; Quercetin.
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