Pegmolesatide Ameliorates Indoxyl Sulfate-Induced Cardiomyocyte Hypertrophy Through Modulating the EPOR-CD131-Dependent JAK2/STAT3 Signaling Pathway

Background: Cardiovascular events remain the leading cause of mortality in chronic kidney disease (CKD). Pegmolesatide(P), a novel long-acting EPO receptor modulator, shows cardiovascular benefits in clinical studies. This study aims to demonstrates Pegmolesatide suppressed the formation of EPOR-CD131 heterodimer and explore its cardioprotective mechanisms against indoxyl sulfate (IS)-induced cardiomyocyte hypertrophy. Methods: H9c2 cardiomyocytes were grouped into phenotypic experiments (vehicle, IS, IS+P, P) and RNA sequencing was performed to identify dysregulated signaling pathways. Mechanistic exploration groups supplemented with CD131 agonist ARA290, STAT3 activator Colivelin, or STAT3 inhibitor Stattic for rescue experiments. Analyses included realtime-qPCR/Western blot for cardiac hypertrophy markers and EPOR-CD131/JAK2/STAT3 axis components, phalloidin staining for cell size and co-immunoprecipitation (Co-IP) for EPOR-CD131 heterodimerization. Results: Pegmolesatide attenuated IS-induced cardiomyocyte hypertrophy, as evidenced by suppressed expression of cardiac hypertrophy markers (ANP, BNP, and β-MHC), reduced cell surface area, and improved cytoskeletal organization(P < 0.05). Mechanistically, Pegmolesatide upregulated EPOR expression while suppressing CD131 expression and the activation of the JAK2/STAT3 signaling. Co-IP analysis demonstrated that Pegmolesatide suppressed the formation of EPOR-CD131 heterodimer. Rescue experiments demonstrated that the cardioprotective effects of Pegmolesatide were reversed by CD131 agonist ARA290 or STAT3 activator Colivelin. Notably, combined treatment with ARA290 and STAT3 inhibitor Stattic partially restored its anti-hypertrophic activity. Conclusion: Pegmolesatide exerts protective effects against IS-induced cardiomyocyte hypertrophy by inhibiting the EPOR-CD131/JAK2/STAT3 signaling axis and may represent a promising therapeutic strategy.