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Mechanistic insights and therapeutic potential of sphingosine‑1‑phosphate in the development of pulmonary fibrosis (Review)

  • Authors:
    • Yanling Qin
    • Chenqi Tang
    • Sen Tan
    • Guangnan Liu
  • View Affiliations / Copyright

    Affiliations: Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530007, P.R. China
    Copyright: © Qin et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 137
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    Published online on: March 18, 2026
       https://doi.org/10.3892/mmr.2026.13847
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Abstract

Pulmonary fibrosis represents a group of chronic, progressive lung disorders arising from diverse etiological factors. Its defining pathological feature is the excessive deposition of collagen, which ultimately results in irreversible distortion of the lung parenchyma. Current therapeutic strategies can slow disease progression but are insufficient to halt it completely. Sphingosine‑1‑phosphate (S1P) is a bioactive sphingolipid metabolite that binds to sphingosine‑1‑phosphate receptors (S1PRs) to regulate numerous vital intracellular metabolic pathways associated with cell proliferation, survival and apoptosis. The present reviewsummarizedthe molecular network through which S1P contributes to the pathogenesis of pulmonary fibrosis, outlines existing pharmacological modulators of the S1P pathway anddiscussedtheir potential therapeutic value in treating this condition.
View Figures

Figure 1

Synthesis, degradation and transport
of S1P. This figure depicts the intracellular synthesis,
degradation and transport of S1P, leading to extracellular
signaling. Sphingomyelinases catalyzes the conversion of
sphingomyelin to produce Cer, which is then converted into Sph by
ceramidase. S1P can be generated by SphK1 and SphK2, while S1P
produced by SphK2 in the nucleus inhibits HDAC activity. Following
S1P generation, SPL degrades it into phosphor-ethanolamine and
hexadecenal, or it is exported out of the cell by Spns2 and ABC,
acting on extracellular S1PRs via autocrine or paracrine
mechanisms. By binding to different receptors, S1P regulates
numerous physiological and pathological processes. ‘→’ represents
‘activation’; ‘—|’ represents ‘inhibition’.S1P,
sphingosine-1-phosphate; Sph, sphingosine; SphK1, sphingosine
kinase 1; SphK2 sphingosine kinase 2; HDAC, histone deacetylase;
S1PRs, sphingosine-1-phosphate receptors; Spns2, spinster homolog
2; ABC, ATP-binding cassette.

Figure 2

Mechanisms of S1P in Pulmonary
Fibrosis. S1P drives the progression of pulmonary fibrosis by
regulating multiple key pathological processes, including
inflammatory responses, FMT, EMT, autophagy and oxidative stress.
‘→’ represents ‘activation’; ‘—|’ represents ‘inhibition’. S1P,
Sph1-phosphate; Sph, sphingosine; SphK1, Sph kinase 1; CFTR, cystic
fibrosis transmembrane conductance regulator; NF-κB, nuclear factor
κB; NLRP3, NOD-like receptor family pyrin domain-containing 3;
IL-1β, interleukin-1β; TNF-α, tumor necrosis factor α; PI3K/AKT,
phosphoinositide 3-kinase/protein kinase B; STAT3, signal
transducer and activator of transcription 3; FMT,
fibroblast-to-myofibroblast transition; ECM, extracellular matrix;
ROCK1, Rho-associated coiled-coil containing protein kinase;
TGF-β1, transforming growth factor-beta 1; EMT,
epithelial-to-mesenchymal transition; Dpr1, Dapper1; TCF/LEF,
T-cell factor/lymphoid enhancer-binding factor; CREB1, cyclic
AMP-responsive element-binding protein 1; ROS, reactive oxygen
species; mtROS, Mitochondrial reactive oxygen species: JNK, c-Jun
N-terminal kinase; RhoA, Ras homolog family member A; YAP,
Yes-associated protein.
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Copy and paste a formatted citation
Spandidos Publications style
Qin Y, Tang C, Tan S and Liu G: Mechanistic insights and therapeutic potential of sphingosine‑1‑phosphate in the development of pulmonary fibrosis (Review). Mol Med Rep 33: 137, 2026.
APA
Qin, Y., Tang, C., Tan, S., & Liu, G. (2026). Mechanistic insights and therapeutic potential of sphingosine‑1‑phosphate in the development of pulmonary fibrosis (Review). Molecular Medicine Reports, 33, 137. https://doi.org/10.3892/mmr.2026.13847
MLA
Qin, Y., Tang, C., Tan, S., Liu, G."Mechanistic insights and therapeutic potential of sphingosine‑1‑phosphate in the development of pulmonary fibrosis (Review)". Molecular Medicine Reports 33.5 (2026): 137.
Chicago
Qin, Y., Tang, C., Tan, S., Liu, G."Mechanistic insights and therapeutic potential of sphingosine‑1‑phosphate in the development of pulmonary fibrosis (Review)". Molecular Medicine Reports 33, no. 5 (2026): 137. https://doi.org/10.3892/mmr.2026.13847
Copy and paste a formatted citation
x
Spandidos Publications style
Qin Y, Tang C, Tan S and Liu G: Mechanistic insights and therapeutic potential of sphingosine‑1‑phosphate in the development of pulmonary fibrosis (Review). Mol Med Rep 33: 137, 2026.
APA
Qin, Y., Tang, C., Tan, S., & Liu, G. (2026). Mechanistic insights and therapeutic potential of sphingosine‑1‑phosphate in the development of pulmonary fibrosis (Review). Molecular Medicine Reports, 33, 137. https://doi.org/10.3892/mmr.2026.13847
MLA
Qin, Y., Tang, C., Tan, S., Liu, G."Mechanistic insights and therapeutic potential of sphingosine‑1‑phosphate in the development of pulmonary fibrosis (Review)". Molecular Medicine Reports 33.5 (2026): 137.
Chicago
Qin, Y., Tang, C., Tan, S., Liu, G."Mechanistic insights and therapeutic potential of sphingosine‑1‑phosphate in the development of pulmonary fibrosis (Review)". Molecular Medicine Reports 33, no. 5 (2026): 137. https://doi.org/10.3892/mmr.2026.13847
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