Multi-omics and experimental analysis unveil the key components in Scutellaria baicalensis Georgi to alleviate hepatic fibrosis via regulating cPLA2-mediated arachidonic acid metabolism

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Abstract
Scutellaria baicalensis Georgi, a traditional Chinese herb, is known for its various biological effects, including antibacterial, anti-inflammatory, antioxidative, and antitumor properties. However, the function and mechanisms of methanol extract of Scutellaria baicalensis Georgi (MESB) in treating hepatic fibrosis remain unclear. This study utilized a CCl4-induced mouse model of hepatic fibrosis to assess the effects of MESB through histopathological analysis and serum tests. The anti-fibrosis mechanism of MESB was investigated using qPCR, Western blotting, RNA interference, proteomics, and metabolomics. Spatial metabolomics identified key components of MESB in liver tissue, while molecular docking determined their targets. Treatment with MESB alleviated hepatic pathological changes and reversed hepatic fibrosis in the CCl4-induced models, as evidenced by decreased collagen fibers deposition, reduced expression of hepatic fibrosis markers COL1A1, FN, and PAI-1, and lowered serum levels of AST and ALT. In vitro, MESB inhibited the proliferation of LX-2 cells and the expression of hepatic fibrosis markers. Furthermore, MESB intervention modulated various pathways, particularly those involved in metabolic pathways. Subsequent metabolomics analysis demonstrated that MESB disrupted glycerophospholipid metabolism and suppressed arachidonic acid metabolism. MESB downregulated the expression of cPLA2 in LX-2 cells, leading to decreased production of arachidonic acid and its downstream inflammatory mediators. Meanwhile, MESB inhibited the expression of cPLA2 and its downstream NF-κB pathway in the liver tissues of models induced by CCl4. Additionally, silencing cPLA2 markedly reduced the expressions of COL1A1, FN, and PAI-1. Spatial metabolomics analysis confirmed the penetration of baicalein, wogonin and wogonoside into liver tissue. Further results indicated that baicalein and wogonin inhibited the expression of cPLA2, while baicalin and wogonoside do not exhibit this effect. Moreover, molecular docking suggested that baicalein and wogonin possess the potential to directly interact with cPLA2. This study reveals that MESB is crucial in preventing hepatic fibrosis via the cPLA2-mediated arachidonic acid metabolic pathway, highlighting its key active components as potential drugs for fibrosis treatment.
Funding Information
  • National Natural Science Foundation of China (82100131, 82004168, 81973567)
  • Natural Science Foundation Project of Chongqing, Chongqing Science and Technology Commission (CSTB2023NSCQ-MSX0136)
  • Science and Technology Research Program of Chongqing Municipal Education Commission (KJQN202215101, KJZD-K202315101)
  • CQMU Program for Youth Innovation in Future Medicine (W0066)

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