Selective JAK-1 Inhibitor Upadacitinib and Peptide PD29 Modulate the JAK and TGF-β/Smad Signaling Pathways Reducing Experimental Dermal Fibrosis

Abstract

This study investigates the antifibrotic and anti-inflammatory effects of Janus kinase (JAK) inhibitors and the PD29 peptide in the context of systemic sclerosis (SSc), a condition characterized by dermal thickening, chronic inflammation, and excessive extracellular matrix deposition. Pulmonary arterial hypertension (PAH) and pulmonary fibrosis represent serious and often fatal complications associated with SSc. The pathogenesis of SSc involves dysregulation of immune responses and aberrant activation of signaling pathways, including TGF beta/Smad. The antifibrotic properties of upadacitinib, a selective JAK1 inhibitor, and PD29 peptide were evaluated using a bleomycin-induced SSc mouse model and primary human lung fibroblasts. Both agents, administered individually or in combination, significantly attenuated dermal thickening, myofibroblast transdifferentiation, collagen deposition, and activation of the TGF-beta 1 signaling axis. In vivo and in vitro analyses demonstrated that upadacitinib and PD29 downregulated key fibrotic markers, including alpha-SMA, JAK1, TGF-beta 1, Smad2, and collagen-1, at both the gene and protein levels. Furthermore, treatment significantly reduced systemic inflammatory cytokines, including IL-6 and TNF-alpha. Notably, combination therapy exhibited a more pronounced effect compared to monotherapy. These findings suggest that upadacitinib and PD29 exert potent antifibrotic and anti-inflammatory effects through suppression of TGF-beta 1-mediated Smad2/3 signaling, predominantly via inhibition of JAK1 activation. Consequently, JAK inhibitors and PD29 represent promising therapeutic candidates for the management of fibrosis in systemic sclerosis.