Bidirectional cellular senescence crosstalk in MASLD: mechanisms, disease progression, and treatment strategies
- 1The Second Clinical Medical College, Henan University of Chinese Medicine
- 2Department of Hepatology and Gastroenterology, Henan Provincial Hospital of Chinese Medicine
- 3College of Acupuncture-Moxibustion and Tuina, Henan University of Chinese Medicine
Abstract
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.
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BibTeX
@article{shi2026bidirectional,
title = {{Bidirectional cellular senescence crosstalk in MASLD: mechanisms, disease progression, and treatment strategies}},
author = {Jinchao Shi and Changpu Zhao and Lei Luo and Haoran Wang and Pu Wei and Xiaojing Wang and Zhiwan Tong and Shunyi Zhu and Qing Zhao and Runyu Li and Jia Yan},
journal = {Frontiers in Endocrinology},
year = {2026},
month = nov,
doi = {10.3389/fendo.2026.1971381},
url = {https://www.frontiersin.org/articles/10.3389/fendo.2026.1971381/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Bidirectional cellular senescence crosstalk in MASLD: mechanisms, disease progression, and treatment strategies
AU - Jinchao Shi
AU - Changpu Zhao
AU - Lei Luo
AU - Haoran Wang
AU - Pu Wei
AU - Xiaojing Wang
AU - Zhiwan Tong
AU - Shunyi Zhu
AU - Qing Zhao
AU - Runyu Li
AU - Jia Yan
PY - 2026
DA - 2026/11/02
JO - Frontiers in Endocrinology
DO - 10.3389/fendo.2026.1971381
UR - https://www.frontiersin.org/articles/10.3389/fendo.2026.1971381/full
AB - 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.
SN - 1664-2392
ER -