Work

Impaired immune surveillance of senescent hepatocytes in MASLD: SASP signaling and fibrogenic progression

Year: 2026

Type: review

Abstract: 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 Mini 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. As a narrative review, 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 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.

Source: Frontiers in Immunology

DOI: 10.3389/fimmu.2026.1982821

Authors: Shuhao Cheng, Yinan Zhao, Wei Wang

Institution: Qinghai University

Language: English

Topic: Liver Disease Diagnosis and Treatment

Subfield: Hepatology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,801