Repurposing methimazole to promote coronary collateral circulation through MAPK1-mediated macrophage polarization via ferroptosis

Rationale: Coronary collateral circulation (CCC) is essential for myocardial recovery after infarction, yet effective strategies to enhance CCC formation are scarce. In this study, we aimed to identify potential FDA-approved drugs that can promote CCC after MI injury. Methods: Candidate drugs were screened through multiple analyses using cMap and public CCC-related databases. Male C57BL/6J mice underwent myocardial infarction (MI) surgery, and 3D micro-CT imaging and immunostaining for smooth muscle actin (SMA) in the watershed region of the heart were employed to evaluate CCC formation. Cardiac function was assessed through Masson's trichrome staining and cardiac ultrasonography. Macrophage polarization was analyzed using flow cytometry, qRT‒PCR, and immunostaining. Additionally, a macrophage and THP-1 cell coculture system was established to simulate the in vivo microenvironment, and mitochondrial morphology was assessed using electron microscopy. Results: Our screen revealed that methimazole (MMI) efficiently promotes CCC formation by driving the polarization of macrophages from the proinflammatory M1-like phenotype to the proangiogenic M2-like phenotype. In vitro, MMI enhanced the differentiation of THP-1 cells into M2-like macrophages and increased VEGFA secretion. Mechanistically, molecular docking studies confirmed a direct interaction between MMI and MAPK1, leading to the suppression of the MAPK1/ROS axis and inhibition of ferroptosis, which facilitated M2 polarization. Furthermore, in vivo, honokiol (HK), a MAPK activator, reversed the effects of MMI on CCC, confirming the pivotal role of the MAPK1 pathway. Conclusions: This study reveals a novel therapeutic role for MMI in promoting CCC formation following MI through the modulation of macrophage polarization via the MAPK1/ROS axis-mediated inhibition of ferroptosis. These findings highlight the potential of MMI as a strategy for enhancing cardiac repair and advancing collateral circulation therapies for ischemic heart disease.