Targeting Cellular Senescence: A New Therapeutic Axis in Chronic Liver Disease

Jiarui Li; Ze Xiang; Yunyang Xu; Xingyu Luo; Yao Jiang; Yingchen Huang; Zhe Yang; Ronggao Chen; Xiao Xu

doi:10.1016/j.eng.2026.02.019

Engineering ›› :202602019 DOI: 10.1016/j.eng.2026.02.019

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research-article

Targeting Cellular Senescence: A New Therapeutic Axis in Chronic Liver Disease

Jiarui Li ^a^,^#
, Ze Xiang ^a^,^#
, Yunyang Xu ^a^,^#
, Xingyu Luo ^b^,^#
, Yao Jiang ^c
, Yingchen Huang ^d
, Zhe Yang ^b^,^*
, Ronggao Chen ^e^,^f^,^*
, Xiao Xu ^g^,^h^,^*

Author information +

^a School of Medicine, Zhejiang University, Hangzhou 310058, China

^b Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital, Zhejiang Shuren University School of Medicine, Hangzhou 310022, China

^c School of Basic Medical Sciences and Forensic Medicine, Hangzhou Medical College, Hangzhou 310059, China

^d The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310053, China

^e NHC Key Laboratory of Combined Multi-Organ Transplantation, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China

^f Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China

^g Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China

^h Institute of Organ Transplantation, School of Medicine, Zhejiang University, Hangzhou 310008, China

^* yangzhe_0201730@163.com (Zhe Yang),

11618331@zju.edu.cn (Ronggao Chen),

zjxu@zju.edu.cn (Xiao Xu)

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Abstract

Cellular senescence, a state of irreversible cell cycle arrest, is increasingly recognized as a key pathological driver of the progression of chronic liver diseases from metabolic dysfunction and fibrosis to hepatocellular carcinoma. While initially acting as a tumor-suppressive mechanism to eliminate damaged cells, the chronic accumulation of senescent cells creates a proinflammatory, profibrotic microenvironment through the senescence-associated secretory phenotype (SASP), thereby promoting tissue damage. This review examines the context-dependent mechanisms of cellular senescence across a range of chronic liver diseases, including metabolic, immune-mediated, viral, and malignant conditions. Building on these mechanisms, we critically assess the therapeutic landscape—from the selective clearance of senescent cells to novel strategies that modulate the senescence program—highlighting both their promise and current limitations. Despite the generally promising preclinical results, the clinical translation of senotherapies faces significant hurdles, including the heterogeneity of senescence, a lack of specific biomarkers, and potential off-target effects. Overcoming these challenges through emerging technologies will be crucial to harnessing senescence as a new therapeutic axis for chronic liver disease.

Keywords

Cellular senescence / Chronic liver disease / Senotherapy

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Jiarui Li, Ze Xiang, Yunyang Xu, Xingyu Luo, Yao Jiang, Yingchen Huang, Zhe Yang, Ronggao Chen, Xiao Xu. Targeting Cellular Senescence: A New Therapeutic Axis in Chronic Liver Disease. Engineering 202602019 DOI:10.1016/j.eng.2026.02.019

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