Bidirectional cellular senescence crosstalk in MASLD: mechanisms, disease progression, and treatment strategies

Metabolic dysfunction-associated steatotic liver disease (MASLD) is not simply a disorder of hepatocyte lipid storage. As metabolic stress persists, damaged hepatocytes and non-parenchymal cells can enter senescent or senescence-like states that reshape the hepatic microenvironment. This review discusses how senescent hepatocytes, hepatic stellate cells (HSCs), liver sinusoidal endothelial cells (LSECs), and immune cells interact during progression from MASLD to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, and hepatocellular carcinoma (HCC). Lipotoxicity, oxidative stress and organelle stress, impaired autophagy, and DNA damage promote hepatocyte senescence and senescence-associated hepatocyte-specific gene signatures (SHGS)-defined phenotypes. Senescence-associated secretory phenotype (SASP) factors, damage-associated molecular patterns, extracellular vesicles (EVs), and matrix-derived signals then sustain reciprocal loops with macrophages and HSCs while also shaping LSEC-centered vascular and immune crosstalk, amplifying inflammation, fibrosis, sinusoidal dysfunction, and failure of immune clearance. Importantly, HSC senescence is context-dependent. Transient arrest may inhibit matrix production, whereas persistent senescent HSCs can promote inflammation and immune escape. We also consider senolytics, senomorphics, restoration of immune surveillance, metabolic and organelle repair, and cell-specific delivery. Because senescence varies across cell types and disease stages, clinical translation will require the identification of relevant cell states using multiple markers and spatial analysis, as well as biomarkers and trial endpoints that distinguish general metabolic improvement from direct disruption of senescence networks.