Senescent hepatic stellate cells drive inflammation and disease progression in MASH (Review).

Abstract

Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by steatosis, inflammation, hepatocellular injury and fibrosis, with the capacity to progress to cirrhosis and hepatocellular carcinoma. Recent evidence highlights cellular senescence, particularly in hepatic stellate cells (HSCs) as a key regulator of MASH pathogenesis. Senescent HSCs exhibit a context-dependent duality whereby, while transient senescence limits fibrosis through cell-cycle arrest, matrix degradation and enhanced immune clearance, persistent senescence under chronic metabolic and inflammatory stress drives disease progression. Through an expanded senescence-associated secretory phenotype (SASP), senescent HSCs exacerbate inflammation, promote extracellular matrix deposition, alter immune responses and facilitate malignant transformation. The present review summarizes the molecular mechanisms inducing HSC senescence, including lipotoxicity, oxidative stress, DNA damage, mitochondrial dysfunction and impaired autophagy. The mechanisms by which SASP factors mediate crosstalk between senescent HSCs and other cell types are discussed, including hepatocytes, macrophages, T cells and natural killer cells, collectively altering the inflammatory and fibrotic microenvironment of MASH. Finally, emerging therapeutic strategies targeting cellular senescence are highlighted, such as senolytics, senomorphics and biomarker-guided interventions, which may offer promising avenues for modifying the course of MASH and preventing disease progression.