IL‐37 Modulates Myocardial Calcium Handling via the p‐STAT3/SERCA2a Axis in HF‐Related Engineered Human Heart Tissue

Abstract Interleukin‐37 (IL‐37) is a potent anti‐inflammatory cytokine belonging to the IL‐1 family. This study investigates the regulatory mechanism and reparative effects of IL‐37 on HF‐related human induced pluripotent stem cells derived cardiomyocytes (hiPSC‐CMs) and engineered human heart tissue subjected to hypoxia and H 2 O 2 treatment. The contractile force and Ca 2+ conduction capacity of the tissue are assessed using a stretching platform and high‐resolution fluorescence imaging system. This investigation reveals that IL‐37 treatment significantly enhances cell viability, calcium transient levels, contractile force, and Ca 2+ conduction capacity in HF‐related hiPSC‐CMs and engineered human heart tissue. Notably, IL‐37 facilitates the upregulation of sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) through enhancing nuclear p‐STAT3 levels. This effect is mediated by the binding of p‐STAT3 to the SERCA2a promoter, providing a novel insight on the reparative potential of IL‐37 in HF. IL‐37 demonstrates its ability to enhance systolic function by modulating myocardial calcium handling via the p‐STAT3/SERCA2a axis in HF‐related engineered human heart tissue (as shown in schematic diagram).