Cellular Senescence in Fatty Liver Disease
Fatty liver disease, or at least the non-alcohol induced side of fatty liver disease, more properly known as metabolic dysfunction-associated steatotic liver disease (MASLD) is largely an outcome of obesity. Obesity is now known to promote an accelerated age-related accumulation of senescent cells in many tissues. It is not surprising to find cellular senescence in liver cells as an important mechanism in the progression of MASLD to more severe and ultimately fatal liver conditions. Treating the consequences of obesity with senotherapeutics does not appear a priority for the research and development community, but in fairness a great many more severe conditions have not yet made it onto that still short priority list either. There are only so many researchers and entrepreneurs in the field, and senotherapeutics can in principle treat a very large number of conditions, given the importance of cellular senescence in aging.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is sustained not only by lipid overload and hepatocellular injury but also by maladaptive responses to persistent metabolic stress. Cellular senescence has emerged as a candidate mechanism linking metabolic stress to persistent inflammation and fibrosis. This short review aims to examine how hepatocyte senescence develops and persists in MASLD, how senescent hepatocytes interact with immune surveillance, and how senescence-associated secretory phenotype (SASP) signaling contributes to fibrotic remodeling. We synthesized recent human, animal, and in vitro evidence, prioritizing mechanistic studies directly addressing hepatocyte senescence, immune cell interactions, SASP signaling, and fibrosis, while retaining landmark studies where they provided essential mechanistic context.
Current evidence indicates that senescent hepatocytes accumulate in experimental and human MASLD and can influence macrophages, hepatic stellate cells, liver sinusoidal endothelial cells, and neighboring hepatocytes. Under conditions of effective immune surveillance, senescence may remain transient and contribute to the removal of damaged cells. In a chronically injured liver, however, continued generation of senescent hepatocytes, altered immune-cell function, and persistent SASP signaling may favor their retention and promote inflammatory and fibrogenic remodeling. Important uncertainties remain, including the lack of universal senescence markers, limited direct evidence for defective senescent-hepatocyte clearance in human MASLD, and the context-dependent effects of senescence across hepatic cell types.
Overall, available evidence supports hepatocyte senescence as a plausible contributor to MASLD progression, but its pathogenic importance appears to depend on cellular context, immune competence, and the duration of the senescent state. Defining these conditions will be important for developing senescence-directed therapies without disrupting beneficial repair responses.