Combined All-trans Retinoic Acid and Rosiglitazone Alleviates Scleroderma Fibrosis by Suppressing the STAT3/Th17 Axis

<h3>Background/Aim:</h3> Effective disease-modifying therapies for systemic sclerosis (scleroderma) remain a major clinical challenge. While all-trans retinoic acid (ATRA) and the PPARγ agonist rosiglitazone (RGZ) possess individual anti-fibrotic properties, their combined therapeutic potential and underlying mechanisms in scleroderma are unexplored. <h3>Materials and Methods:</h3> This study investigated the efficacy and mechanisms of combined ATRA and RGZ therapy in a bleomycin (BLM)-induced murine scleroderma model and TGF-β1-stimulated NIH-3T3 fibroblasts. Pathological changes were assessed <i>via</i> histological analyses, quantitative PCR, ELISA, and western blotting. <h3>Results:</h3> BLM-challenged mice exhibited pronounced dermal thickening, excessive collagen accumulation, and elevated Th17-related inflammatory responses. Strikingly, the ATRA+RGZ combination therapy significantly outperformed either monotherapy, robustly restoring normal skin architecture, reducing collagen density, and suppressing the expression of fibrotic mediators (TGF-β1, COL1a1) and Th17-associated factors (IL-17A, IL-6). <i>In vitro</i> experiments confirmed that this combination directly prevented TGF-β1-induced fibroblast-to-myofibroblast transition. Mechanistically, the dual therapy synergistically inhibited STAT3 phosphorylation and RORγt nuclear translocation. Importantly, pharmacological reactivation of STAT3 by Colivelin completely abrogated the anti-fibrotic and anti-inflammatory benefits of the combination <i>in vivo</i>. <h3>Conclusion:</h3> The concurrent administration of ATRA and RGZ exerts superior protection against scleroderma fibrosis by converging on the inhibition of the STAT3/Th17 signaling axis. This study provides a compelling mechanistic rationale for repurposing and combining ATRA and RGZ as a translational strategy for scleroderma treatment.