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Background <p>Novel therapies are urgently needed for diffuse cutaneous systemic sclerosis (dcSSc). Aberrant JAK/STAT signaling drives fibrosis, but JAK inhibitors’ effects on vascular pathology and potential synergy with endothelial-derived exosomes remain unclear.</p> Methods <p>Utilizing bleomycin (BLM)-induced human skin fibroblast (HSF) activation and hypoxia-impaired human umbilical vein endothelial cell (HUVEC) models, we investigated the anti-fibrotic mechanisms of the JAK1/JAK2 inhibitor Baricitinib. Functional assays assessed proliferation, migration, tube formation, extracellular matrix (ECM) deposition, and cytokine production. Conditioned media (CM) and exosomes from Baricitinib-treated HUVECs were applied to BLM-HSFs to evaluate paracrine/exosomal roles.</p> Results <p>Baricitinib (6 nmol/L) directly inhibited BLM-induced HSF proliferation, Collagen I/III, α-SMA expression, and actin polymerization. In hypoxia-damaged HUVECs, Baricitinib (54 nmol/L) restored proliferation, migration, tube formation, and suppressed JAK/STAT3 hyperactivation. Crucially, CM from Baricitinib-treated HUVECs significantly attenuated BLM-HSF fibrotic activation, an effect abolished by exosome inhibitor GW4869. Exosomes from Baricitinib-treated HUVECs exhibited enhanced uptake by HSFs and superior suppression of proliferation, cytoskeletal reorganization, and profibrotic marker expression compared to control exosomes; these effects were diminished by exosome disruption.</p> Conclusion <p>Baricitinib alleviates skin fibrosis via a dual mechanism: direct suppression of fibroblast activation and indirect mitigation through the “reprogramming” of HUVEC-derived exosomes. By rescuing endothelial dysfunction and enhancing the anti-fibrotic cargo of endothelial exosomes, Baricitinib interrupts the vascular damage-fibrosis cycle in dcSSc. This identifies endothelial exosomes as key mediators of JAK inhibitor efficacy, offering a novel therapeutic paradigm.</p>

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Baricitinib ameliorates skin fibrosis via direct fibroblast suppression and endothelial exosome-mediated paracrine signaling

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月20日

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  • Zhanying Hou,
  • Xiufeng Zhao,
  • Fang Liu,
  • Shi Xu

摘要

Background

Novel therapies are urgently needed for diffuse cutaneous systemic sclerosis (dcSSc). Aberrant JAK/STAT signaling drives fibrosis, but JAK inhibitors’ effects on vascular pathology and potential synergy with endothelial-derived exosomes remain unclear.

Methods

Utilizing bleomycin (BLM)-induced human skin fibroblast (HSF) activation and hypoxia-impaired human umbilical vein endothelial cell (HUVEC) models, we investigated the anti-fibrotic mechanisms of the JAK1/JAK2 inhibitor Baricitinib. Functional assays assessed proliferation, migration, tube formation, extracellular matrix (ECM) deposition, and cytokine production. Conditioned media (CM) and exosomes from Baricitinib-treated HUVECs were applied to BLM-HSFs to evaluate paracrine/exosomal roles.

Results

Baricitinib (6 nmol/L) directly inhibited BLM-induced HSF proliferation, Collagen I/III, α-SMA expression, and actin polymerization. In hypoxia-damaged HUVECs, Baricitinib (54 nmol/L) restored proliferation, migration, tube formation, and suppressed JAK/STAT3 hyperactivation. Crucially, CM from Baricitinib-treated HUVECs significantly attenuated BLM-HSF fibrotic activation, an effect abolished by exosome inhibitor GW4869. Exosomes from Baricitinib-treated HUVECs exhibited enhanced uptake by HSFs and superior suppression of proliferation, cytoskeletal reorganization, and profibrotic marker expression compared to control exosomes; these effects were diminished by exosome disruption.

Conclusion

Baricitinib alleviates skin fibrosis via a dual mechanism: direct suppression of fibroblast activation and indirect mitigation through the “reprogramming” of HUVEC-derived exosomes. By rescuing endothelial dysfunction and enhancing the anti-fibrotic cargo of endothelial exosomes, Baricitinib interrupts the vascular damage-fibrosis cycle in dcSSc. This identifies endothelial exosomes as key mediators of JAK inhibitor efficacy, offering a novel therapeutic paradigm.