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Beyond hepatic stellate cell heterogeneity: Resolving fibrosis, restoring regeneration (Review)

  • Authors:
    • Chang Gao
    • Guiqing Chen
    • Hongyan Jia
    • Hong Zhu
    • Yun Cai
    • Dakai Yang
    • Kai Zhao
  • View Affiliations / Copyright

    Affiliations: Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China, School of Life Sciences, Jiangsu University Jingjiang College, Zhenjiang, Jiangsu 212013, P.R. China, Department of Gastroenterology, Jintan Affiliated Hospital of Jiangsu University, Changzhou, Jiangsu 213200, P.R. China
    Copyright: © Gao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 62
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    Published online on: January 14, 2026
       https://doi.org/10.3892/ijmm.2026.5733
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Abstract

Hepatic stellate cells (HSCs), specialized liver‑resident pericytes, play pivotal roles in both liver fibrogenesis and regeneration. Following hepatic injury, quiescent HSCs undergo activation and transdifferentiation into myofibroblasts, which drive tissue remodeling and scar formation. Recent advances have uncovered notable phenotypic and functional heterogeneity within HSC populations, with distinct subsets displaying context‑dependent activation states and specialized functions across diverse liver pathologies. The present review synthesizes current insights into the dynamic spectrum of HSC phenotypes and the molecular mechanisms governing their plasticity, emphasizing the mechanisms through which niche‑specific signaling, epigenetic regulation and metabolic reprogramming coordinate their functional diversity. The present review further discuss emerging therapeutic strategies that leverage this heterogeneity to selectively target pathogenic HSC subsets, while preserving their homeostatic roles, thereby opening new avenues for precision anti‑fibrotic therapies and liver regeneration.

View Figures

Figure 1

The molecular mechanisms regulating
HSC heterogeneity. (A-a) HSC heterogeneity is spatially regulated
by local microenvironmental cues. While CaHSCs residing in hypoxic,
nutrient-poor pericentral regions rapidly produce ECM upon
stimulation, PaHSCs in oxygen- and nutrient-rich periportal areas
preferentially proliferate to support regeneration. (A-b) ECM
stiffness regulates HSC phenotypic diversity. ECM-dense pericentral
regions activate mechanosensitive YAP/TAZ pathways in HSCs,
reinforcing ECM deposition and fibrosis, while softer periportal
areas promote HSC migration and proliferation through suppressing
matrix production. (B) HSC subsets are induced through distinct
signaling pathways, driving their differentiation into
inflammatory, fibrogenic, pro-regenerative, or senescent
phenotypes. (C) The phenotypic plasticity of HSCs is governed by
epigenetic reprogramming. While H3K9 demethylation induces
TLR4/NF-κB signaling and activates fibrogenic HSC phenotypes,
mechanical cues from the tumor microenvironment amplify histone
acetylation at fibrotic loci, resulting in upregulation of α-SMA
and CTGF, thus driving pro-fibrotic and pro-tumor HSC states. (D)
The phenotypic diversity of HSCs stems from their remarkable
metabolic plasticity. Following injury, enhanced GLUT1-mediated
glucose uptake and PKM2-driven glycolytic flux fuels mitochondrial
oxidative phosphorylation to support myofibroblast differentiation.
Meanwhile, accumulated ROS production activates NF-κB/NLRP3
inflammasome pathways, driving HSC toward pro-inflammatory fate.
Moreover, the metabolic reprogramming redirects pyruvate toward
lipid synthesis, leading to lipid droplet reformation, which
sustains fibrotic activity through PPARγ suppression and TGF-β
activation. HSC, hepatic stellate cell; ECM, extracellular matrix;
YAP, yes-associated protein; TAZ, transcriptional coactivator with
PDZ-binding motif; TLR4, Toll-like receptor 4; α-SMA, α smooth
muscle actin; CTGF, connective tissue growth factor; ROS, reactive
oxygen species; NLRP3, NOD-like receptor family pyrin domain
containing 3; PPARγ, peroxisome proliferator-activated receptor γ;
PV, portal vein; CV, central vein; CaHSC, central vein-associated
HSC; PaHSC, portal vein-associated HSC; pro-Reg HSC,
pro-regeneration HSCs; sHSC, senescent HSC; KDM4D, lysine
demethylase 4D; GLUT1, glucose transporter type 1; PKM2, pyruvate
kinase M2.

Figure 2

Therapeutic strategies targeting
HSCs. (A) Inhibit HSC activation via targeting key signaling
pathways using small-molecule inhibitors such as PDGF antagonists
or TGF-β inhibitors. During the early stages of HSC activation,
induction of autophagy by pharmacological inhibitors like
chloroquine or genetic ablation of autophagy-related genes such as
ATG5/7 attenuate collagen deposition and HSC activation. (B)
Clearance of aHSC can be achieved by the crosstalk between immune
cells and aHSC, or pharmacological interventions using
small-molecule inhibitors such as IKK inhibitors, resulting in
apoptosis of aHSC. (C) Targeting specific subsets of activated HSCs
using NP-engineered vesicles carrying drugs or siRNA. For example,
NP-AEAA, utilizes aminoethyl anisamide surface modifications to
selectively target Sig-1R that are upregulated on activated HSCs in
NASH progression. Another clinically validated targets include
VitA-depleted aHSCs, which can be selectively addressed using
VitA-coupled liposomal NPs. Furthermore, BMS-986263, a LNP
encapsulating siRNA against HSP47 associated with collagen
production, utilizes VitA to target aHSCs in fibrotic livers. (D)
aHSCs can be reprogrammed into alternative phenotypes to reduce
their profibrotic effects. The application of HDACIs induces aHSC
transition into sHSC by upregulating HMGA1, while Tcf21 promotes
reversion of aHSC to an inactivated state. Moreover, co-expression
of TFs such as FOXA3, GATA4, HNF1A, and HNF4A enables HSC
transdifferentiation into hepatocyte-like cells. HSC, hepatic
stellate cell; PDGF, platelet-derived growth factor; qHSC,
quiescent HSCs; aHSC, activated HSCs; NP, nanoparticle; AEAA,
aminoethyl anisamide; Sig-1R, sigma-1 receptor; VitA, vitamin A;
ACC, acetyl-CoA carboxylase; HSP47, heat shock protein 47; HDACIs,
histone deacetylase inhibitors; HMGA1, high mobility group AT-hook
1; TF, transcription factor; Tcf21, transcription factor 21; iHSC,
inactivated HSCs; Hep-like cells, hepatocyte-like cells; FOXA3,
forkhead box A3; GATA4, GATA binding protein 4; HNF, hepatocyte
nuclear factor.
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Copy and paste a formatted citation
Spandidos Publications style
Gao C, Chen G, Jia H, Zhu H, Cai Y, Yang D and Zhao K: <p>Beyond hepatic stellate cell heterogeneity: Resolving fibrosis, restoring regeneration (Review)</p>. Int J Mol Med 57: 62, 2026.
APA
Gao, C., Chen, G., Jia, H., Zhu, H., Cai, Y., Yang, D., & Zhao, K. (2026). <p>Beyond hepatic stellate cell heterogeneity: Resolving fibrosis, restoring regeneration (Review)</p>. International Journal of Molecular Medicine, 57, 62. https://doi.org/10.3892/ijmm.2026.5733
MLA
Gao, C., Chen, G., Jia, H., Zhu, H., Cai, Y., Yang, D., Zhao, K."<p>Beyond hepatic stellate cell heterogeneity: Resolving fibrosis, restoring regeneration (Review)</p>". International Journal of Molecular Medicine 57.3 (2026): 62.
Chicago
Gao, C., Chen, G., Jia, H., Zhu, H., Cai, Y., Yang, D., Zhao, K."<p>Beyond hepatic stellate cell heterogeneity: Resolving fibrosis, restoring regeneration (Review)</p>". International Journal of Molecular Medicine 57, no. 3 (2026): 62. https://doi.org/10.3892/ijmm.2026.5733
Copy and paste a formatted citation
x
Spandidos Publications style
Gao C, Chen G, Jia H, Zhu H, Cai Y, Yang D and Zhao K: <p>Beyond hepatic stellate cell heterogeneity: Resolving fibrosis, restoring regeneration (Review)</p>. Int J Mol Med 57: 62, 2026.
APA
Gao, C., Chen, G., Jia, H., Zhu, H., Cai, Y., Yang, D., & Zhao, K. (2026). <p>Beyond hepatic stellate cell heterogeneity: Resolving fibrosis, restoring regeneration (Review)</p>. International Journal of Molecular Medicine, 57, 62. https://doi.org/10.3892/ijmm.2026.5733
MLA
Gao, C., Chen, G., Jia, H., Zhu, H., Cai, Y., Yang, D., Zhao, K."<p>Beyond hepatic stellate cell heterogeneity: Resolving fibrosis, restoring regeneration (Review)</p>". International Journal of Molecular Medicine 57.3 (2026): 62.
Chicago
Gao, C., Chen, G., Jia, H., Zhu, H., Cai, Y., Yang, D., Zhao, K."<p>Beyond hepatic stellate cell heterogeneity: Resolving fibrosis, restoring regeneration (Review)</p>". International Journal of Molecular Medicine 57, no. 3 (2026): 62. https://doi.org/10.3892/ijmm.2026.5733
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