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

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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13075-025-03710-9.