Biomedical & Pharmacology Journal, December 2021. Vol. 14(4), p. 1841-1862 Published by Oriental Scientific Publishing Company © 2021 This is an Open Access article licensed under a Creative Commons license: Attribution 4.0 International (CC-BY). Liver Fibrosis: Underlying Mechanisms and Innovative Therapeutic Approach : A Review Article Sally A El Awdan and Gihan F. Asaad* Pharmacology Department, National Research Center, ElBohoos St. Dokki, Giza 12622, Egypt. *Corresponding Author E-mail:dr_g.asaad@yahoo.com https://dx.doi.org/10.13005/bpj/2283 (Received: 31 August 2021; accepted: 08 December 2021) Liver fibrosis is considered “a pathological repairing process in liver injuries leading to extracellular cell matrix (ECM) accumulation evidencing chronic liver diseases”. Chronic viral hepatitis, alcohol consumption, autoimmune diseases as well as non-alcoholic steatohepatitis are from the main causes of liver fibrosis (Lee et al., 2015; Mieli-Vergani et al., 2018). Hepatic stellate cells (HSCs) exist in the sinus space next to the hepatic epithelial cells as well as endothelial cells (Yin et al., 2013). Normally, HSCs are quiescent and mainly participate in fat storage and in the metabolism of vitamin A. HSCs are produced during liver injury and then transformed into myofibroblasts. The activated HSCs resulted in a sequence of events considered as marks fibrosis. The activation of HSCs mostly express alpha smooth muscle actin (a-SMA). Moreover, ECM is synthesized and secreted by HSCs that affects markedly the structure and function of the liver tissue leading to fibrosis (Tsuchida et al., 2017; Han et al., 2020). Hence, activated HSCs are attracting attention as potential targets in liver fibrosis. Many signaling molecules are involved in HSCs activation first and foremost, platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-ß) (Tsuchida et al., 2017; Wang et al., 2020c) as interfering the PDGF or TGF-ß signaling pathways is a growing field for liver fibrosis treatment. Keywords: Liver fibrosis; Hepatic stellate cells; PDGF; TGF-ß; a-SMA. The ECM proteins’ - particularly collagen type 1, - accumulation distorts the hepatic archi- tecture through the formation of a fbrous wound, followed by the expansion of spherical areas of cells called nodules then hardening of the tissue. A series of events follows resulting in cirrhosis. Liver cirrhosis causes hepatocellular dysfunction, hepatocellular carcinoma (HCC) and hence, hepatic failure (Giannitrapani et al., 2014). Liver fbrosis involves parenchymal, non- parenchymal liver cells and infltrating immune cells. Cell death activates the infammatory and pro-fibrogenic pathways that triggers fibrosis progression, as well as the possibility of reversing the process that aids in fbrosis resolution (Lee et al., 2015). Hepatic macrophages, injured hepatocytes, lymphocytes and endothelial cells leads to the induction of HSC. The dead hepatocytes release of reactive oxygen species, damage- associated molecular patterns (DAMPs) which stimulate macrophages (Kupfer cells) to release proinfammatory biomarkers and pro-fbrogenic markrs, (Yang et al., 2012). Other pro-infammatory factors include gut-derived pathogen-associated molecular