Activated hepatic stellate cells and hepatic microenvironment (aHSC/HME)

Activated hepatic stellate cells (aHSCs) are the primary drivers of liver fibrosis, transforming from quiescent vitamin A-storing cells into proliferative, contractile myofibroblasts following liver injury (Friedman, 2008, Physiological Reviews). This activation is triggered by various stimuli within the hepatic microenvironment, including oxidative stress, inflammatory cytokines from Kupffer cells, and changes in the extracellular matrix (ECM) composition (Tsuchida & Friedman, 2017, Nature Reviews Gastroenterology & Hepatology). The hepatic microenvironment itself consists of a complex interplay between sinusoidal endothelial cells, immune cells, and the ECM, which collectively sustain the fibrogenic response (Pellicoro et al., 2014, Nature Reviews Immunology). Pharmacological targeting of this system aims to inhibit the signaling pathways that drive HSC activation, such as the TGF-beta and PDGF pathways, or to promote the resolution of fibrosis by inducing HSC senescence or apoptosis (Higashi et al., 2017, Advanced Drug Delivery Reviews). Interacting drugs like Cenicriviroc and Selonsertib attempt to modulate these cellular responses by targeting chemokine receptors and stress-activated kinases, respectively (Friedman et al., 2018, Nature Reviews Drug Discovery). While targeting the microenvironment offers a holistic approach to treating chronic liver diseases like NASH and cirrhosis, the lack of specificity to the liver and the essential role of these cells in normal tissue repair present significant therapeutic challenges (Schuppan & Kim, 2013, Journal of Hepatology).

Other names

Activated HSCsLiver myofibroblastsPerisinusoidal cellsIto cellsFibrotic liver niche

Inhibition of pro-fibrotic signaling pathways (e.g., TGF-beta, PDGF), modulation of chemokine receptors to reduce inflammatory cell recruitment, and direct inhibition of extracellular matrix cross-linking enzymes.