Daidzein alleviates CCl4- and BDL-induced liver fibrosis via suppressing the integrin alphaVbeta1/YAP signaling

Abstract

Liver fibrosis is a pathological process characterized by the excessive deposition of diffuse extracellular matrix in the liver, serving as a reparative response of the body to chronic liver injury. Daidzein (DAI) is an isoflavone compound primarily derived from leguminous plants, such as soybeans and kudzu root. Numerous studies have demonstrated its significant anti-inflammatory and antioxidant properties; however, the extent of its role in anti-hepatic fibrosis remains uncertain. This study aimed to investigate whether DAI exerts a therapeutic effect on liver fibrosis and to elucidate its underlying molecular mechanisms. In this study, we primarily investigated the anti-hepatic fibrosis effects of DAI. We established two mouse models of liver fibrosis through intraperitoneal injection of carbon tetrachloride (CCl₄) and bile duct ligation (BDL). Following serum-free treatment, we administered transforming growth factor β1 to stimulate LX-2 cells, thereby creating a model for the activation of hepatic stellate cell (HSC) lines. DAI mitigated liver injury induced by CCl₄ and BDL, as evidenced by decreased serum levels of aspartate aminotransferase, alanine aminotransferase, and liver hydroxyproline. Furthermore, DAI also diminished the inflammatory response associated with CCl₄ and BDL. Additionally, DAI reduced the expression of α-smooth muscle actin and type I collagen, alpha 1, demonstrating anti-hepatic fibrosis effects by lowering the expression of integrin alphaV, integrin beta1, and YAP, while simultaneously increasing the protein expression of phosphorylated YAP (Ser 397). The use of the YAP inhibitor verteporfin in LX-2, along with YAP silencing treatment, confirmed that DAI inhibits the activation of HSCs through the regulation of YAP. This study demonstrated that DAI can mitigate liver injury and inflammatory responses induced by CCl₄ and BDL. It inhibited the activation of HSCs and reduced liver fibrosis by targeting the integrin/YAP signaling pathway. These findings suggested that DAI may serve as a potential candidate for anti-hepatic fibrosis chemical drugs.