MiR‐126‐3p and MiR‐195‐5p as Novel Therapeutic Attenuators of Liver Fibrosis by Targeting the IRS1/PI3K Signalling Pathway

ABSTRACT Background & Aims Hepatic fibrosis is a progressive response to chronic liver injury. A key event in the development of hepatic fibrosis is the activation of hepatic stellate cells (HSCs); emerging research indicates that microRNAs play crucial roles in regulating HSCs activation. However, the specific roles of miR‐126‐3p (miR‐126) and miR‐195‐5p (miR‐195) in liver fibrosis remain inadequately understood. Methods We examined the expression of miR‐126 and miR‐195 in activated HSCs, fibrotic liver tissues from animal models, and blood samples from patients with liver disease. The effects on cell proliferation and migration were investigated by MTT, colony formation assay, cell wound healing assay, and Transwell assay. Finally, we evaluated the effect of miR‐126 and miR‐195 on the progression of liver fibrosis in mice. Results We revealed that miR‐126 and miR‐195 were markedly downregulated in activated HSCs, fibrotic liver tissues from animal models, and blood samples from patients with liver diseases. Functional experiments demonstrated that the overexpression of miR‐126 and miR‐195 significantly inhibited the proliferation, migration, and fibrotic markers expression in HSCs. Conversely, silencing miR‐126 and miR‐195 produced the opposite effects. Further mechanistic studies showed that miR‐126 and miR‐195 downregulate insulin receptor substrate 1 (IRS1) or phosphoinositide 3‐kinase regulatory subunit 2 (PIK3‐R2), respectively, thereby inhibiting the pro‐fibrotic signalling pathway (IRS1/PI3K) and regulating the functions of HSCs. Importantly, in vivo experiments demonstrated that miR‐126 and miR‐195 markedly alleviated CCL 4 ‐induced hepatic fibrosis in mice. Conclusions Our results unravel that miR‐126 and miR‐195 inhibit liver fibrosis by suppressing the IRS/PI3K pathway.