Hepatocellular injury initiates liver inflammation through the release of damage-associated signals. These signals, as well as cytokines and chemokines released by activated embryonic Kupffer cells (emKCs), recruit circulating immune cells to the liver, where they undergo pronounced phenotypical changes. Monocytes differentiate into inflammatory, scar-associated macrophages, and the adaptive immune response shifts toward Th2/17 immunity. Cytokines, growth factors, and damage-associated signals eventually drive the activation of quiescent hepatic stellate cells (qHSCs) toward an activated (aHSC), proliferative, extracellular matrix (ECM)-producing and contractile myofibroblast-like phenotype. Phenotypical changes are accompanied and dependent on pronounced metabolic adaptations, including increased glycolysis, activation of lipogenic pathways, and metabolic stress responses, including oxidative and endoplasmic reticulum stress, as well as autophagy and ferroptosis, and changes in nuclear receptor signaling. ADP, adenosine diphosphate; CCL, C-C motif ligand; CXCL, C-X-C motif ligand; DAMPs, damage-associated molecular patterns; DNL,de novolipogenesis; ER, endoplasmic reticulum; FFA, free fatty acid; FXR, farnesoid X receptor; HMGB1, high mobility group box 1; (q/a)HSC, (quiescent/activated) hepatic stellate cell; IL, interleukin; LXR, liver X receptor; MMP, matrix metalloproteinase; mtDNA, mitochondrial DNA; oxLDL, oxidized low-density lipoprotein; OxPhos, oxidative phosphorylation; PAMPs, pathogen-associated molecular patterns; STAT-3, signal transducer and activator of transcription 3; PPAR, peroxisome proliferator-activated receptor; TGF-β, transforming growth factor beta. Created withBioRender.com.
