Ab1148 Exploring Prss23 as a Novel Therapy Target for Skin Fibrosis in Systemic Sclerosis

Background: Systemic Sclerosis (SSc) is an autoimmune disease characterized by fibrosis in skin and internal organs, significantly impacting patients' lives. A key feature of SSc, skin fibrosis, is central to the disease's progression and prognosis. Despite ongoing research, the complex pathophysiology of SSc is not fully understood. In this context, Serine Protease 23 (PRSS23) has emerged as a noteworthy molecule. Recent RNA-seq findings indicate its upregulation in the fibrotic skin tissues of SSc patients, suggesting a crucial role in fibrogenesis. Investigating PRSS23's functions could reveal new insights into SSc's pathology and offer avenues for novel treatments. Objectives: This study aims to identify the expression of PRSS23 in skin fibrosis associated with SSc and to investigate the potential of PRSS23 as a novel therapeutic target for this condition. Methods: We analyze the GSE58095 database to assess PRSS23 expression levels and their correlation with the modified Rodnan skin score (mRSS). Immunohistochemistry analysis of PRSS23 expression in skin tissues of SSc patients and healthy individuals, complemented by evaluating PRSS23 levels in extracted fibroblasts (n=6). Knockdown of PRSS23 in fibroblasts derived from SSc patient skin tissues, followed by stimulation with transforming growth factor-β (TGF-β), and subsequent assessment of ECM-related gene expression (n=3). Intradermal injection of PRSS23 siRNA for the treatment of bleomycin (BLM)-induced skin fibrosis (n=6). Results: In the GSE58095 dataset, PRSS23 levels in SSc patient skin tissues were elevated compared to healthy controls (p<0.001) and positively associated with mRSS scores (R=0.4096, p=0.0014). Further experiments confirm that expression levels of PRSS23 are elevated in the skin tissues and primary fibroblasts of SSc patients, when compared with those in healthy controls. Finally, we discovered that PRSS23 knockdown can inhibit the expression of collagen I, collagen III, fibronectin in skin fibroblasts of SSc patients and improve collagen deposition, skin thickening, and collagen fber alignment in the BLM-induced skin fibrosis model (Figure1). Conclusion: Utilizing clinical samples, this study reveals elevated PRSS23 expression in the skin tissues of SSc patients. Importantly, targeting PRSS23 has been shown to suppress ECM-related gene expression in fibroblasts and alleviate BLM-induced skin fibrosis. This significant finding could open new therapeutic pathways for fibrosis treatment and deepen researchers' understanding of fibrotic mechanisms. REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests: None declared.