Hepatic stellate cell activation and fibrogenic signaling (HSC activation)

Hepatic stellate cell (HSC) activation and fibrogenic signaling represent the central driver of liver fibrosis (Friedman, 2008, Physiol Rev). In a healthy liver, HSCs are quiescent cells that store vitamin A; however, upon chronic injury from alcohol, viral hepatitis, or metabolic stress, they undergo a phenotypic transformation into proliferative, contractile, and fibrogenic myofibroblasts (Tsuchida & Friedman, 2017, Nat Rev Gastroenterol Hepatol). This activation is mediated by a complex network of signaling pathways, most notably the Transforming Growth Factor-beta (TGF-β) pathway, which stimulates the production of extracellular matrix (ECM) components like Collagen type I (Puche et al., 2013, Compr Physiol). Activated HSCs are the primary source of excessive ECM deposition, leading to the replacement of functional liver parenchyma with scar tissue, eventually resulting in cirrhosis. Therapeutic strategies currently under investigation aim to inhibit this activation process, promote the reversion of myofibroblasts to a quiescent state, or induce their apoptosis to halt or reverse the progression of liver fibrosis (Higashi et al., 2017, J Gastroenterol).

Other names

HSC activationHepatic fibrogenesisMyofibroblastic transformation of HSCsLiver fibrogenic signaling

Therapeutic intervention involves modulating various nodes within the signaling network, including inhibition of TGF-beta signaling, activation of nuclear receptors (FXR, PPAR), and blockade of chemokine receptors (CCR2/CCR5) to prevent HSC recruitment and activation (Tsuchida & Friedman, 2017, Nat Rev Gastroenterol Hepatol).