Esomeprazole Inhibits Proliferation of Scleroderma Fibroblasts via Cell Cycle Regulation

Mohammad Aasif Khan¹Shaheer Koniyan¹Manisha Ahir²Anil Jegga³Maureen D Mayes⁴David Gius⁵Justin Leung⁵Mark D Bonnen⁶Sydney B Montesi⁷Yohannes T Ghebre^5*

• ¹Department of Radiation Oncology, UT Health, San Antonio, San Antonio, United States
• ²Department of Radiation Oncology, Baylor College of Medicine, Houston, United States
• ³Division of Biomedical Informatics, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, United States
• ⁴Department of Internal Medicine, Division of Rheumatology, The University of Texas Health Science Center at Houston John P and Katherine G McGovern Medical School, Houston, United States
• ⁵Department of Radiation Oncology, Mays Cancer Center, UT Health, San Antonio, San Antonio, United States
• ⁶7Department of Radiation Oncology, Tufts University School of Medicine, Boston, United States
• ⁷6Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, United States

Abstract 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 by interfering with cell cycle regulation in 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 were decreased following esomeprazole treatment. In conclusion, esomeprazole induces G1 phase arrest by upregulating p21 and downregulating CDK1 and CDK2, thereby inhibiting fibroblast proliferation. These data provide important insights into how esomeprazole regulates fibroblast proliferation in scleroderma and suggest that it may represent a potential therapeutic intervention.