Hepatocyte intracellular signaling pathways related to oxidative stress, inflammation, and fibrosis

Hepatocyte intracellular signaling pathways related to oxidative stress, inflammation, and fibrosis encompass a complex array of molecular interactions that drive the progression of chronic liver injury. These pathways are activated by various stimuli, including lipotoxicity and viral infection, leading to the production of reactive oxygen species (ROS) and the activation of stress-responsive kinases like JNK and p38 MAPK (Cichoz-Lach & Michalak, 2014). Central to the inflammatory response is the NF-kappaB signaling cascade, which promotes the expression of pro-inflammatory cytokines that recruit immune cells to the liver (Luedde & Schwabe, 2011). Simultaneously, the TGF-beta/SMAD pathway acts as a primary driver of fibrosis by stimulating the activation of hepatic stellate cells into collagen-producing myofibroblasts (Meng et al., 2016). Therapeutic intervention in these pathways aims to restore cellular homeostasis by targeting specific nodes, such as the farnesoid X receptor (FXR) or thyroid hormone receptor beta (THR-beta), to reduce steatosis and subsequent downstream signaling (Younossi et al., 2019). Understanding the integration of these pathways is crucial for developing effective treatments for conditions like metabolic dysfunction-associated steatohepatitis (MASH).

Other names

Hepatic stress and fibrosis signalingHepatocyte injury pathwaysLiver fibrogenesis cascadesNASH signaling network

Modulation of specific signaling nodes, such as agonism of the farnesoid X receptor (FXR) or thyroid hormone receptor beta (THR-beta), and inhibition of apoptosis signal-regulating kinase 1 (ASK1), to reduce oxidative damage, suppress pro-inflammatory cytokine release, and inhibit the activation of hepatic stellate cells into myofibroblasts.