Hepatic stellate cell activation and apoptosis signaling network (HSC activation/apoptosis pathways)

Hepatic stellate cells (HSCs) are the primary cellular drivers of liver fibrosis, transdifferentiating from quiescent, vitamin A-storing cells into activated, proliferative, and contractile myofibroblasts in response to chronic liver injury (Friedman, 2008, Physiol Rev). This activation process is orchestrated by a complex network of signaling pathways, most notably the Transforming Growth Factor-beta (TGF-beta)/Smad and Platelet-Derived Growth Factor (PDGF) pathways, which promote the excessive synthesis and deposition of extracellular matrix (ECM) proteins (Tsuchida & Friedman, 2017, Nat Rev Gastroenterol Hepatol). Conversely, the resolution of liver fibrosis is associated with the clearance of activated HSCs through apoptosis or reversion to a quiescent-like state. Apoptosis in HSCs can be triggered by extrinsic signals via death receptors like TRAIL and Fas, or through the intrinsic mitochondrial pathway involving the modulation of Bcl-2 family proteins (Kisseleva & Brenner, 2021, J Clin Invest). Pharmacological targeting of these pathways aims to either prevent the activation of HSCs or selectively induce their death to halt or reverse fibrotic progression. However, the pleiotropic nature of these signaling molecules presents significant challenges for achieving liver-specific therapeutic effects without systemic toxicity (Trautwein et al., 2015, J Hepatol).

Other names

HSC activationHepatic stellate cell transdifferentiationLiver myofibroblast signalingIto cell activation

Therapeutic intervention involves the inhibition of pro-fibrotic signaling pathways such as TGF-beta/Smad and PDGF/PI3K, the antagonism of chemokine receptors (e.g., CCR2/CCR5), or the induction of apoptosis in activated HSCs via death receptor ligands or BH3 mimetics (Friedman, 2008; Tsuchida & Friedman, 2017).