Esomeprazole Inhibits Proliferation of Scleroderma Fibroblasts via Cell Cycle Regulation

Scleroderma is a complex autoimmune disease characterized by abnormal fibroblast proliferation and excessive collagen deposits in the skin and internal organs. We previously showed that esomeprazole, an FDA-approved drug for gastric disorders, may prevent dermal fibrosis. Here, we demonstrate that esomeprazole exerts anti-proliferative effects on scleroderma fibroblasts by interfering with cell cycle regulation. To test this, we evaluated the antiproliferative effect of esomeprazole and the underlying molecular mechanisms using primary fibroblasts derived from patients with scleroderma. BrdU incorporation, flow cytometry, immunofluorescence, Western blot analysis, RNA sequencing, and functional enrichment analysis all showed a decrease in fibroblast proliferation. In addition, esomeprazole inhibited the proliferation of scleroderma fibroblasts in a dose-dependent manner, as measured by the Ki-67 marker. Intriguingly, esomeprazole arrested fibroblasts in the G1 phase of the cell cycle, resulting in a reduction of cells in the S phase. Expression of p21, a known inhibitor of cyclin-dependent kinases (CDKs), was elevated, while CDK1 and CDK2 levels decreased following esomeprazole treatment. These data provide important insights into how esomeprazole regulates fibroblast proliferation in scleroderma and suggest that it may represent a potential therapeutic intervention for scleroderma. Overall design: Primary dermal fibroblasts from two limited scleroderma male donors (SScF_P01and P02) were cultured under identical conditions and treated with esomeprazole (0, 10, 20, 50, 100 uM) for 24h. RNA Seq profiling was done on extracted mRNA. All patient samples were gifted by our collaborator Maureen D Mayes, Department of Internal Medicine, The University of Texas Health Science Center at Houston.