Biochemical and biophysical research communications · 2025
ITGA8 deficiency in hepatic stellate cells attenuates CCl4-Induced liver fibrosis via suppression of COL11A1.
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Yan Xuzhen, Han Qi, Wu Wenyue, Li Hong, Zhang Wen, Wang Yiwen, Chen Wei, Yang Aiting, You Hong
Аннотация
BACKGROUND AND OBJECTIVE: Liver fibrosis is a pathological process driven by chronic liver injury, characterized by excessive extracellular matrix (ECM) deposition due to hepatic stellate cell (HSC) activation. Integrins are critical regulators of ECM remodeling and HSC activation, yet the role of integrin α8(ITGA8) in liver fibrosis remains unclear. This study aims to investigate the function and underlying mechanisms of HSC-derived ITGA8 in liver fibrosis and evaluate the therapeutic potential of ITGA8-targeted intervention.
METHODS: A CCl4-induced mouse liver fibrosis model and public database analysis were used to assess ITGA8 expression and localization in liver fibrosis. AAV2/6-shItga8 was utilized to selectively silence HSC-derived ITGA8, and its effects on HSC activation and ECM accumulation were examined. In addition, in vitro ITGA8 knockdown combined with proteomic analysis was performed to explore the molecular mechanisms linking ITGA8 to ECM remodeling.
RESULTS: ITGA8 expression was significantly upregulated in fibrotic liver tissues across different etiologies, with a strong colocalization with HSCs. Silencing ITGA8 using AAV2/6-shItga8 effectively reduced liver fibrosis, as indicated by decreased hepatic inflammation, lower serum ALT levels, reduced inflammatory cell infiltration, and downregulated expression of pro-inflammatory cytokines. Fibrosis markers, including Sirius Red staining, type I collagen deposition, and α-SMA expression, were all reduced upon Itga8 silencing. Proteomic analysis revealed that ITGA8 regulates liver fibrosis through the ECM-receptor interaction pathway, with COL11A1 identified as a key downstream target. ITGA8 knockdown significantly suppressed COL11A1 expression, and reduced HSC-mediated collagen contraction, suggesting that ITGA8 contributes to ECM cross-linking and fibrosis progression via COL11A1 regulation.
CONCLUSION: This study demonstrates that HSC-derived ITGA8 promotes ECM accumulation and liver fibrosis progression by regulating COL11A1. Targeted silencing of ITGA8 via AAV2/6-shItga8 effectively alleviates liver fibrosis, providing new insights into ITGA8 as a potential therapeutic target for antifibrotic treatment.
METHODS: A CCl4-induced mouse liver fibrosis model and public database analysis were used to assess ITGA8 expression and localization in liver fibrosis. AAV2/6-shItga8 was utilized to selectively silence HSC-derived ITGA8, and its effects on HSC activation and ECM accumulation were examined. In addition, in vitro ITGA8 knockdown combined with proteomic analysis was performed to explore the molecular mechanisms linking ITGA8 to ECM remodeling.
RESULTS: ITGA8 expression was significantly upregulated in fibrotic liver tissues across different etiologies, with a strong colocalization with HSCs. Silencing ITGA8 using AAV2/6-shItga8 effectively reduced liver fibrosis, as indicated by decreased hepatic inflammation, lower serum ALT levels, reduced inflammatory cell infiltration, and downregulated expression of pro-inflammatory cytokines. Fibrosis markers, including Sirius Red staining, type I collagen deposition, and α-SMA expression, were all reduced upon Itga8 silencing. Proteomic analysis revealed that ITGA8 regulates liver fibrosis through the ECM-receptor interaction pathway, with COL11A1 identified as a key downstream target. ITGA8 knockdown significantly suppressed COL11A1 expression, and reduced HSC-mediated collagen contraction, suggesting that ITGA8 contributes to ECM cross-linking and fibrosis progression via COL11A1 regulation.
CONCLUSION: This study demonstrates that HSC-derived ITGA8 promotes ECM accumulation and liver fibrosis progression by regulating COL11A1. Targeted silencing of ITGA8 via AAV2/6-shItga8 effectively alleviates liver fibrosis, providing new insights into ITGA8 as a potential therapeutic target for antifibrotic treatment.