Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Astragalus polysaccharides alleviate cantharidin-induced liver injury by inhibiting the S100A8/A9-mediated TLR4/NF-κB inflammatory pathway.
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Tang Wenchao, Shen Qin, Du Xingyan, Yu Jia, Sa Zongge, Xiao Yuanyuan
Аннотация
BACKGROUND: Cantharidin (CTD), a potent anti-tumor compound from traditional medicine, has its clinical application restricted by severe hepatotoxicity. Astragalus polysaccharides (APS), the primary active components of the food-medicine homologous herb Astragalus membranaceus, are recognized for their hepatoprotective properties.
PURPOSE: This study aimed to elucidate the molecular mechanism by which APS protects against CTD-induced liver injury.
METHODS: In vivo and in vitro models of CTD-induced liver injury were established. The protective effects of APS were evaluated by serum biochemistry, histopathology, and ultrastructural observation. RNA-sequencing was employed to screen for key targets, which were subsequently validated using qRT-PCR, Western blot, and immunohistochemistry. The cellular origin of S100A8/A9 was identified by immunofluorescence co-localization. The functional role of S100A8/A9 was confirmed via siRNA-mediated gene knockdown. The effect of APS on the anti-tumor activity of CTD was evaluated in human hepatocellular carcinoma cell lines HepG2 and Huh7.
RESULTS: APS (characterized by a weight-average molecular weight of 35.002 kDa) ameliorated CTD-induced liver injury, reducing biochemical markers and histopathological damage. RNA-seq identified S100A8/A9 as key targets whose CTD-induced upregulation was reversed by APS. Mechanistically, APS significantly inhibited CTD-induced neutrophil and macrophage infiltration in the liver, and immunofluorescence co-localization confirmed that the elevated S100A8/A9 was mainly derived from infiltrating neutrophils. APS downregulated S100A8/A9 expression, thereby inhibiting the TLR4/NF-κB pathway and the release of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6). Critically, S100A8/A9 knockdown confirmed their pivotal role in the inflammatory response and demonstrated a synergistic protective effect when combined with APS. Importantly, APS did not impair the anti-proliferative and pro-apoptotic effects of CTD on human hepatocellular carcinoma cells; instead, it exhibited synergistic anti-tumor activity with CTD in HepG2 cells.
CONCLUSION: APS alleviates CTD-induced hepatotoxicity by downregulating the S100A8/A9-mediated TLR4/NF-κB inflammatory cascade, primarily through inhibiting neutrophil recruitment. Furthermore, APS enhances rather than compromises the anti-tumor efficacy of CTD in vitro. These findings support the development of APS as a therapeutic adjuvant to enhance the safety of CTD-based chemotherapy.
PURPOSE: This study aimed to elucidate the molecular mechanism by which APS protects against CTD-induced liver injury.
METHODS: In vivo and in vitro models of CTD-induced liver injury were established. The protective effects of APS were evaluated by serum biochemistry, histopathology, and ultrastructural observation. RNA-sequencing was employed to screen for key targets, which were subsequently validated using qRT-PCR, Western blot, and immunohistochemistry. The cellular origin of S100A8/A9 was identified by immunofluorescence co-localization. The functional role of S100A8/A9 was confirmed via siRNA-mediated gene knockdown. The effect of APS on the anti-tumor activity of CTD was evaluated in human hepatocellular carcinoma cell lines HepG2 and Huh7.
RESULTS: APS (characterized by a weight-average molecular weight of 35.002 kDa) ameliorated CTD-induced liver injury, reducing biochemical markers and histopathological damage. RNA-seq identified S100A8/A9 as key targets whose CTD-induced upregulation was reversed by APS. Mechanistically, APS significantly inhibited CTD-induced neutrophil and macrophage infiltration in the liver, and immunofluorescence co-localization confirmed that the elevated S100A8/A9 was mainly derived from infiltrating neutrophils. APS downregulated S100A8/A9 expression, thereby inhibiting the TLR4/NF-κB pathway and the release of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6). Critically, S100A8/A9 knockdown confirmed their pivotal role in the inflammatory response and demonstrated a synergistic protective effect when combined with APS. Importantly, APS did not impair the anti-proliferative and pro-apoptotic effects of CTD on human hepatocellular carcinoma cells; instead, it exhibited synergistic anti-tumor activity with CTD in HepG2 cells.
CONCLUSION: APS alleviates CTD-induced hepatotoxicity by downregulating the S100A8/A9-mediated TLR4/NF-κB inflammatory cascade, primarily through inhibiting neutrophil recruitment. Furthermore, APS enhances rather than compromises the anti-tumor efficacy of CTD in vitro. These findings support the development of APS as a therapeutic adjuvant to enhance the safety of CTD-based chemotherapy.