Pathophysiological Drivers and Molecular Targets for the Reversal of Hepatic Fibrosis

Liver fibrosis is a pathological response to chronic injury, such as viral hepatitis, metabolic disorders, or autoimmune conditions, resulting in the excessive accumulation of extracellular matrix (ECM) proteins. The process is primarily driven by the activation of hepatic stellate cells (HSCs). In response to DAMPs and cytokines such as TGF-β and TNF-α, these cells transition from a quiescent state to an active, collagen-producing myofibroblast phenotype. This environment is further sustained by an imbalance between matrix metalloproteinases (MMPs), which degrade collagen, and tissue inhibitors of metalloproteinases (TIMPs), which inhibit collagen degradation. Without intervention, this structural distortion hinders hepatic blood flow, causing portal hypertension and progressing to cirrhosis. This advanced stage poses severe risks, including hepatocellular carcinoma and liver failure. Understanding these pathways is vital for developing therapies. This review delineates the underlying pathophysiology of hepatic fibrosis and highlights cutting-edge strategies to transition the liver from a state of chronic fibrogenesis toward active matrix resolution.