Compound J27 alleviates obesity-induced cardiomyopathy by targeting JNK2

With the global prevalence of obesity continuing to rise, obesity-induced cardiomyopathy (OCM) has emerged as an important independent driver of heart failure. However, current clinical management remains limited to indirect metabolic interventions, such as weight loss and lipid-lowering therapies, with no disease-modifying treatments that specifically target the pathological mechanisms of OCM. We previously developed J27, a highly selective small-molecule inhibitor of c-Jun N-terminal kinase 2 (JNK2). In this study, we aimed to delineate the isoform-specific role of JNK2 in OCM pathogenesis and to evaluate the therapeutic efficacy and translational potential of J27.

A high-fat diet (HFD) -induced mouse model of OCM was established to assess the therapeutic effects of J27. Cardiac structural and functional alterations were comprehensively evaluated using multimodal histological analyses, biochemical assays, and echocardiography. In parallel, in vitro experiments were performed in cardiomyocytes and macrophages challenged with palmitic acid (PA) to investigate the regulatory effects of J27 on cardiomyocyte injury, calcium homeostasis, and inflammatory activation of immune cells.

In HFD-fed mice, J27 markedly attenuated cardiac hypertrophy and interstitial fibrosis while significantly improving cardiac function in a dose-dependent manner. Mechanistically, J27 partially restored cardiomyocyte calcium handling by inhibiting the JNK2/CaMKIIδ signaling axis, thereby alleviating calcium dysregulation-associated myocardial injury. Concurrently, J27 suppressed macrophage-driven inflammatory responses through inhibition of the JNK2/c-Jun pathway, thereby attenuating cardiomyocyte hypertrophy induced by macrophage-cardiomyocyte crosstalk. Importantly, genetic knockdown of JNK2 abolished the cardioprotective effects of J27, establishing JNK2 as the obligatory molecular target mediating its therapeutic actions and highlighting the central pathological role of the JNK2 isoform in OCM progression.

JNK2 acts as a critical nodal regulator of OCM by coordinately controlling cardiomyocyte calcium homeostasis and macrophage-mediated inflammatory responses. As a potent and highly selective JNK2 inhibitor, J27 confers robust protection against HFD-induced OCM, supporting its promise as a targeted therapeutic candidate for obesity-induced cardiac dysfunction.