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Signalling pathways regulated by FSTL1 in inflammation and potential therapeutic applications (Review)

  • Authors:
    • Changliang Ma
    • Jingxin Li
    • Wenting Jiang
    • Xiaoqiang Chen
    • Jianquan Liu
    • Xu Tao
    • Wencui Li
    • Zhiqin Deng
    • Zhe Zhao
  • View Affiliations / Copyright

    Affiliations: Department of Hand and Foot Surgery, Shenzhen Second People's Hospital/The First Hospital Affiliated to Shenzhen University, Medical Innovation Technology Transformation Centre of Shenzhen Second People's Hospital, Shenzhen, Guangdong 518000, P.R. China, Operating Room, Shenzhen Second People's Hospital/ The First Hospital Affiliated to Shenzhen University, Shenzhen, Guangdong 518000, P.R. China
    Copyright: © Ma et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 86
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    Published online on: February 5, 2026
       https://doi.org/10.3892/ijmm.2026.5757
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Abstract

Follistatin‑like protein 1 (FSTL1), a secreted glycoprotein, serves a key role in regulating various biological processes. The present review explores the molecular mechanisms through which FSTL1 influences inflammation, cellular senescence and tumour progression. As a multifunctional protein with both autocrine and paracrine properties, FSTL1 regulates cell survival, proliferation, differentiation and migration, while also modulating immune responses. Evidence indicates that FSTL1 exerts context‑dependent regulatory effects on pathological conditions by modulating signalling pathways, such as TGF‑β, NF‑κB and MAPK. Furthermore, increased FSTL1 expression has been found in the inflammatory synovial tissues of patients with osteoarthritis and it contributes to nucleus pulposus cell inflammation. In conclusion, the distinctive structural features and widespread expression of FSTL1 position it as a key target for understanding the mechanisms underlying inflammation, senescence and tumourigenesis, providing potential options for novel diagnostic and therapeutic strategies for these conditions.

View Figures

Figure 1

FSTL1-mediated crosstalk between TLR4
and TGF-β signalling pathways in inflammation and fibrosis. This
schematic diagram illustrates the molecular mechanisms by which
FSTL1 orchestrates crosstalk between TLR4 and TGF-β signalling
pathways. Upon binding to cell surface receptors, FSTL1
simultaneously activates multiple downstream signalling cascades.
TLR4 pathway activation: FSTL1 binding to TLR4 triggers
MyD88-dependent signalling, leading to two major downstream
branches: i) TRAF6-TAK1-IKK axis resulting in NF-κB pathway
activation through IκB degradation and nuclear translocation of
p50/p65 heterodimers; ii) MAPKKK-MAPKs cascade activating p38 and
JNK, which converge on AP-1 (c-Fos/Jun) transcription factors.
TGF-β pathway enhancement: FSTL1 promotes TGF-β receptor complex
formation and enhances canonical Smad signalling through Smad2/3
phosphorylation and Smad4 nuclear translocation, while also
activating non-canonical pathways, including the Ras-Raf-MEK-ERK
cascade. Transcriptional outcomes: The convergence of these
pathways results in coordinated transcriptional programs producing:
i) Pro-inflammatory mediators, chemokines and enzymes; ii) fibrotic
mediators including MMPs, pro-fibrotic cytokines and EMT-associated
factors. Pathway interactions: Phosphorylated ERK1/2 and activated
transcription factors (Smad2/3/4 complex, NF-κB, AP-1) coordinate
nuclear gene expression programs that promote both inflammatory
responses and tissue remodelling processes. The diagram
demonstrates how FSTL1 serves as a critical hub protein integrating
immune activation and fibrotic responses through simultaneous
modulation of multiple signalling networks. Created with BioRender.com (Created in BioRender. Deng, Z. (2025)
https://BioRender.com/3o0ydwz). EMT,
epithelial-mesenchymal transition; FSTL1, follistatin-like protein
1; IKK, IκB kinase; iNOS, inducible nitric oxide synthase; MCP1,
monocyte chemoattractant protein-1; MIP, macrophage inflammatory
protein; MMP, matrix metalloproteinase; TLR4, Toll-like receptor
4.

Figure 2

FSTL1 integrates metabolic,
inflammatory and differentiation signalling through the
PI3K/AKT/mTOR and NLRP3 inflammasome pathways. This diagram
delineates the intracellular signalling mechanisms by which FSTL1
regulates cellular metabolism, inflammatory responses and cell fate
decisions. PI3K/AKT/mTORC1 Axis: FSTL1 signalling facilitates
PIP2 to PIP3 at the plasma membrane, a
critical step indicative of PI3K activation. PIP3
recruits and activates PDK1, which in turn phosphorylates and fully
activates AKT. Activated AKT (phosphorylated-AKT) serves as a
central signalling hub, driving the activation of the mTORC1
pathway, a master regulator of anabolic processes. NLRP3
inflammasome activation: Concurrently, FSTL1 stimulation induces
the generation of ROS. Both FSTL1 and ROS contribute to the
assembly and activation of the NLRP3 inflammasome complex. This
multi-protein complex, consisting of NLRP3, the adaptor protein ASC
and pro-caspase-1, leads to the cleavage and activation of
caspase-1. Active caspase-1 then catalyses the maturation and
secretion of the potent pro-inflammatory cytokine IL-1β. FSTL1
enhances electron transport chain activity, which promotes NLRP3
inflammasome activation and IL-1β secretion. Integrated functional
outcomes: The convergence of these FSTL1-initiated signals
orchestrates key cellular responses: Cell proliferation and
survival, MSC differentiation and migration/invasion. Solid arrows
indicate direct activation or conversion processes; tapered lines
represent contributory pathways or functional outcomes. Created
with BioRender.com (Created in BioRender.
Deng, Z. (2025) https://BioRender.com/w34o3gm). ASC,
apoptosis-associated speck-like protein containing a CARD; FSTL1,
follistatin-like protein 1; MSC, mesenchymal stem cell; NLRP3, NLR
family pyrin domain-containing 3; ROS, reactive oxygen species.
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Ma C, Li J, Jiang W, Chen X, Liu J, Tao X, Li W, Deng Z and Zhao Z: <p>Signalling pathways regulated by FSTL1 in inflammation and potential therapeutic applications (Review)</p>. Int J Mol Med 57: 86, 2026.
APA
Ma, C., Li, J., Jiang, W., Chen, X., Liu, J., Tao, X. ... Zhao, Z. (2026). <p>Signalling pathways regulated by FSTL1 in inflammation and potential therapeutic applications (Review)</p>. International Journal of Molecular Medicine, 57, 86. https://doi.org/10.3892/ijmm.2026.5757
MLA
Ma, C., Li, J., Jiang, W., Chen, X., Liu, J., Tao, X., Li, W., Deng, Z., Zhao, Z."<p>Signalling pathways regulated by FSTL1 in inflammation and potential therapeutic applications (Review)</p>". International Journal of Molecular Medicine 57.4 (2026): 86.
Chicago
Ma, C., Li, J., Jiang, W., Chen, X., Liu, J., Tao, X., Li, W., Deng, Z., Zhao, Z."<p>Signalling pathways regulated by FSTL1 in inflammation and potential therapeutic applications (Review)</p>". International Journal of Molecular Medicine 57, no. 4 (2026): 86. https://doi.org/10.3892/ijmm.2026.5757
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Spandidos Publications style
Ma C, Li J, Jiang W, Chen X, Liu J, Tao X, Li W, Deng Z and Zhao Z: <p>Signalling pathways regulated by FSTL1 in inflammation and potential therapeutic applications (Review)</p>. Int J Mol Med 57: 86, 2026.
APA
Ma, C., Li, J., Jiang, W., Chen, X., Liu, J., Tao, X. ... Zhao, Z. (2026). <p>Signalling pathways regulated by FSTL1 in inflammation and potential therapeutic applications (Review)</p>. International Journal of Molecular Medicine, 57, 86. https://doi.org/10.3892/ijmm.2026.5757
MLA
Ma, C., Li, J., Jiang, W., Chen, X., Liu, J., Tao, X., Li, W., Deng, Z., Zhao, Z."<p>Signalling pathways regulated by FSTL1 in inflammation and potential therapeutic applications (Review)</p>". International Journal of Molecular Medicine 57.4 (2026): 86.
Chicago
Ma, C., Li, J., Jiang, W., Chen, X., Liu, J., Tao, X., Li, W., Deng, Z., Zhao, Z."<p>Signalling pathways regulated by FSTL1 in inflammation and potential therapeutic applications (Review)</p>". International Journal of Molecular Medicine 57, no. 4 (2026): 86. https://doi.org/10.3892/ijmm.2026.5757
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