Compound BOZA attenuates fibrosis in systemic sclerosis by modulating the PERK-HNRNPA1 axis.

Endoplasmic reticulum (ER) stress is critically implicated in the pathogenesis of Systemic sclerosis (SSc), yet targeted therapeutic strategies remain limited. Here, we identify a repurposed small-molecule compound BOZA (PubChem CID: 5113653), as a potent antifibrotic agent that alleviates SSc-associated fibrosis by targeting the PERK-HNRNPA1 signaling axis. Mechanistic investigations reveal that BOZA engages the ER stress sensor PERK, suppressing its dimerization and autophosphorylation. Crucially, this inhibition blocks the ER stress-induced destabilization of the RNA-binding protein HNRNPA1. By preserving HNRNPA1 stability, BOZA modulates downstream fibrotic signaling, defining the PERK-HNRNPA1 axis as a functionally relevant regulatory node linking ER stress resolution to antifibrotic activity. Genetic rescue experiments support that BOZA's antifibrotic efficacy is significantly dependent on PERK signaling and requires HNRNPA1 stabilization. In vitro, BOZA effectively suppresses TGF-β-driven fibroblast hyperactivation, proliferation, and migration. In vivo, administration of BOZA significantly attenuates bleomycin-induced dermal and pulmonary fibrosis in mice, partially restoring tissue architecture and significantly reducing collagen deposition. Collectively, our findings identify the PERK-HNRNPA1 axis as a critical mechanism linking ER stress to fibrosis and position BOZA as a promising preclinical modulator for treating SSc.