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Role of cellular senescence in hepatic diseases (Review)

  • Authors:
    • Yunqi Xing
    • Junfeng Zhu
  • View Affiliations / Copyright

    Affiliations: Department of Hepatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, P.R. China
    Copyright: © Xing et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 182
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    Published online on: September 2, 2025
       https://doi.org/10.3892/ijmm.2025.5623
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Abstract

Cellular senescence, a hallmark of aging, is characterized by irreversible, permanent cell cycle arrest accompanied by halted proliferation triggered by endogenous or exogenous stimuli. The accumulation of senescent cells in tissues or organs elicits detrimental effects on adjacent normal cells through their pathogenic senescence‑associated secretory phenotype (SASP), driving secondary senescence, disrupting tissue homeostasis and ultimately exacerbating age‑related pathologies such as types of cancer and neurodegenerative disorders. Hepatic disorders constitute a leading cause of global mortality, imposing considerable healthcare burdens. Robust clinical evidence has now demonstrated a strong correlation between cellular senescence and poor clinical outcomes in various hepatopathies. This intricate yet critical signaling network is dynamically regulated in both physiological homeostasis and chronic hepatic inflammatory conditions. Notably, recent years have witnessed extensive research into pharmacological strategies to deplete senescent cells, inhibit SASP, and target other senescence markers across diverse contexts, thereby establishing the field of senotherapeutics. The present review systematically summarized key molecular pathways and biomarkers of hepatic senescence, while outlining the emerging role of cellular senescence in inflammatory liver disorders. It also discussed the therapeutic potential of senescence‑regulating drugs for liver disease, which could alleviate hepatic inflammation and enhance clinical outcomes.
View Figures

Figure 1

Schematic diagram of the molecular
mechanism of cellular senescence. Diverse endogenous and exogenous
stimuli induce irreversible G1 arrest, triggering
premature senescence. Repeated DNA replication and telomere
shortening initiate DSB/DDR signaling, activating ATM/ATR kinases.
This dysregulates the p53/p21CIP1 and
p16INK4a/Rb pathways and aberrantly activates p62,
NF-κB, MAPK and mTOR signaling. Notably, p62 and ATR kinase exhibit
bidirectional regulation: p62 recruits ATR to sites of DNA
replication stress, enhancing its kinase activity, while
ATR-mediated phosphorylation of p62 promotes its transcriptional
expression and facilitates interaction between phosphorylated p62
and NF-κB. These pathways synergize via crosstalk to drive
senescence, manifesting as enlarged and flattened morphology, Lamin
B1 downregulation, SA-β-Gal activity, cGAS-STING induction and
mitochondrial dysfunction. Senescence is reinforced autocrinely and
propagated paracrinely via SASP factors (inflammatory cytokines,
chemokines, proteases and growth factors), ultimately promoting
tissue destruction, chronic inflammation, fibrosis and
carcinogenesis. ATM, ataxia-telangiectasia mutated; ATR, ATM and
Rad3-related; CCL, CC-chemokine ligand; CXCL, CXC-chemokine ligand;
DDR, DNA damage response; DSB, DNA double-strand break; IL,
interleukin; MAPK, mitogen-activated protein kinase; MMP, matrix
metalloproteinase; mTOR, mechanistic target of rapamycin; mtDNA,
mitochondrial DNA; NF-κB, nuclear factor κ-B; ROS, reactive oxygen
species; SA-β-Gal, senescence-associated β-galactosidase; SASP,
senescence-associated secretory phenotype; TGF-β, transforming
growth factor-beta; TNF-α, tumor necrosis factor-alpha; VEGF,
vascular endothelial growth factor.

Figure 2

Cellular and functional alterations
in liver under aging conditions. Schematic depicts livers in young
(left), aged (middle), and inflamm-aging (right) states, showing
region-specific changes in cellular composition and architecture.
In youth, hepatocytes with microvilli, KCs, quiescent HSCs and
fenestrated LSECs maintain structural integrity. Aging involves
progressive anatomical changes: Fenestrated LSECs disappear in the
space of Disse, capillarization occurs, and SASP factors from
senescent cells activate HSCs, triggering ECM deposition.
Concurrently, activated KCs release inflammatory mediators that
recruit immune cells. Multidirectional interactions among activated
HSCs, KCs, and innate immune cells drive pathological ECM
accumulation and myofibroblast formation. These changes
collectively cause tissue stiffening and immune dysregulation,
establishing a pro-inflammatory microenvironment. Emerging evidence
indicates interdependence of senescence across liver cell types.
ECM, extracellular matrix; HSC, hepatic stellate cell; KC, Kupffer
cell; LSEC, liver sinusoidal endothelial cell; SASP,
senescence-associated secretory phenotype.

Figure 3

Stress responses in liver cellular
senescence and therapeutic pathway approaches. (A) Endogenous and
exogenous insults accumulate in liver tissue throughout aging. (B)
Progressive anatomical and functional changes caused by disease or
persistent injury impair mechanisms maintaining cellular
homeostasis during aging. Concurrently, the liver develops stress
responses including cellular senescence, metabolic reprogramming,
mitochondrial dysfunction, oxidative stress, disrupted protein
homeostasis and epigenetic alterations. Targeting these pathways
may ameliorate age-related pathology. AMPK, adenosine
monophosphate-activated protein kinase; ATP, adenosine
triphosphate; CAT, catalase; ECM, extracellular matrix; ER,
endoplasmic reticulum; ETC, electron transport chain; FXR,
farnesoid X receptor; GPx, glutathione peroxidase; GR, glutathione
reductase; HSC, hepatic stellate cell; LXR, liver X receptor;
mtDNA, mitochondrial DNA; NADPH, nicotinamide adenine dinucleotide
phosphate; ncRNA, non-coding RNA; OXPHOS, oxidative
phosphorylation; PKM2, pyruvate kinase M2; PPAR, peroxisome
proliferator-activated receptor; ROS, reactive oxygen species;
SASP, senescence-associated secretory phenotype; SIRT3, sirtuin 3;
SOD, superoxide dismutase; TCA, tricarboxylic acid cycle.

Figure 4

Immune mechanisms in the pathogenesis
of CHB, ALD and MAFLD. Chronic liver diseases consistently exhibit
disease-related immune dysregulation affecting innate and adaptive
systems. However, each disease displays a distinct inflammatory
signature, characterized by unique recruited cell populations and
expressed bioactive molecules. ALD, alcoholic liver disease; APC,
antigen-presenting cell; CCL, CC-chemokine ligand; CHB, chronic
hepatitis B; CXCL, CXC-chemokine ligand; DAMPs, damage-associated
molecular patterns; DC, dendritic cell; ECM, extracellular matrix;
HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen;
HSC, hepatic stellate cell; IDO, indoleamine 2,3-dioxygenase;
IFN-γ, interferon-gamma; IL, interleukin; KC, Kupffer cell; LPS,
lipopolysaccharide; M1, classically activated macrophage; M2,
alternatively activated macrophage; MAFLD, metabolic
dysfunction-associated fatty liver disease; MDSC, myeloid-derived
suppressor cell; NETs, neutrophil extracellular traps; NF-κB,
nuclear factor kappa-B; NK, natural killer cell; PAMPs,
pathogen-associated molecular patterns; PD-1, programmed cell death
protein 1; SASP, senescence-associated secretory phenotype; TGF,
transforming growth factor; TGF-β, transforming growth factor-beta;
Th, T helper cell; TLR4, Toll-like receptor 4; TNF-α, tumor
necrosis factor-alpha; Treg, regulatory T cell.

Figure 5

Molecular mechanisms underlying
senescence-targeted interventions. Senotherapeutic approaches
involve selectively eliminating senescent cells through apoptosis
induction and suppressing SASP. Several of these interventions and
drugs have shown promising therapeutic efficacy for chronic liver
diseases by targeting cellular senescence. Akt, protein kinase B;
AMPK, adenosine 5′-monophosphate-activated protein kinase; BCL,
B-cell lymphoma; DRI, D-retro-inverso isoform; FOXO4, forkhead box
protein O4; HSP, heat shock protein; IL, interleukin; JAK/STAT,
Janus kinase/signal transducers and activators of transcription;
MDM2, mouse double minute 2; mTOR, mammalian target of rapamycin;
NF-κB, nuclear factor kappa-B; NLRP3, NOD-like receptor family
pyrin domain containing 3; OXPHOS, oxidative phosphorylation; PI3K,
phosphatidylinositol 3-kinase; ROS, reactive oxygen species; SIRT1,
sirtuin 1; SASP, senescence-associated secretory phenotype; TNF-α,
tumor necrosis factor-α.
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Xing Y and Zhu J: Role of cellular senescence in hepatic diseases (Review). Int J Mol Med 56: 182, 2025.
APA
Xing, Y., & Zhu, J. (2025). Role of cellular senescence in hepatic diseases (Review). International Journal of Molecular Medicine, 56, 182. https://doi.org/10.3892/ijmm.2025.5623
MLA
Xing, Y., Zhu, J."Role of cellular senescence in hepatic diseases (Review)". International Journal of Molecular Medicine 56.5 (2025): 182.
Chicago
Xing, Y., Zhu, J."Role of cellular senescence in hepatic diseases (Review)". International Journal of Molecular Medicine 56, no. 5 (2025): 182. https://doi.org/10.3892/ijmm.2025.5623
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Spandidos Publications style
Xing Y and Zhu J: Role of cellular senescence in hepatic diseases (Review). Int J Mol Med 56: 182, 2025.
APA
Xing, Y., & Zhu, J. (2025). Role of cellular senescence in hepatic diseases (Review). International Journal of Molecular Medicine, 56, 182. https://doi.org/10.3892/ijmm.2025.5623
MLA
Xing, Y., Zhu, J."Role of cellular senescence in hepatic diseases (Review)". International Journal of Molecular Medicine 56.5 (2025): 182.
Chicago
Xing, Y., Zhu, J."Role of cellular senescence in hepatic diseases (Review)". International Journal of Molecular Medicine 56, no. 5 (2025): 182. https://doi.org/10.3892/ijmm.2025.5623
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