Key result
Complement C3 and C3aR inhibition improves cardiac function and reduces hypertrophy in diabetic mice.
Why the study?
The pathogenesis of diabetic cardiomyopathy remains incompletely understood and effective targeted therapies are lacking, prompting investigation into the role of complement C3a in its development.
Does inhibiting complement C3a/C3aR signaling with SB290157 or CP40-KK improve cardiac function and inhibit cardiomyocyte PANoptosis in a preclinical model of diabetic cardiomyopathy?
Does inhibiting complement C3a/C3aR signaling with SB290157 or CP40-KK improve cardiac function and inhibit cardiomyocyte PANoptosis in a preclinical model of diabetic cardiomyopathy?
Preclinical evidence demonstrates that complement C3a drives diabetic cardiomyopathy via the C3aR/ERK/PANoptosis pathway, and pharmacological inhibition with SB290157 or CP40-KK preserves cardiac function in diabetic mice.
Answers are grounded in this paper and cite their sources.
No immediate clinical application in diabetic cardiomyopathy; leaves open human validation of C3aR-ERK-PANoptosis targeting.
BACKGROUND Diabetic cardiomyopathy (DCM) is one of the leading causes of death in diabetic patients. However, the pathogenesis of DCM remains incompletely understood, and effective targeted therapies are lacking. This study aims to investigate the role of complement C3a in the development of DCM, providing a novel theoretical foundation for its precise prevention and treatment. METHODS Eight-week-old male C57BL/6 J mice were injected with streptozotocin (STZ) to induce a diabetes model for 26 weeks. The two intervention groups were injected with C3a receptor antagonist (SB290157, 30 mg/kg/d) and novel C3 cleavage inhibitor (CP40-KK, 2 mg/kg/d) by intraperitoneal injection for 8 weeks. Cardiac function/histopathological changes were determined by echocardiogram examination, and Millar catheter system. Human cardiomyocytes (AC16) were employed in vitro. RESULTS C3a was significantly upregulated in the plasma of the STZ-induced DCM model, and PANoptosis plays a critical role in cardiac tissue and cardiomyocytes. The C3a receptor antagonist (SB290157) could significantly improve the cardiac function of diabetic mice, reduce myocardial hypertrophy, and inhibit the activation level of PANoptosis pathway in cardiac tissue. Furthermore, inhibiting the C3aR/ERK pathway could regulate cardiomyocyte PANoptosis by pyroptosis (NLRP3-dependent), apoptosis (caspase-3-dependent), and necroptosis (RIP-dependent) in the DCM model and C3a-treated cardiomyocytes. The novel complement C3 inhibitor CP40-KK exerts comparable therapeutic efficacy to SB290157 in treating DCM at a lower drug dosage. CONCLUSION We demonstrate the crucial role of the C3a/C3aR signaling axis, and CP40-KK treatment was protective in the STZ-induced DCM model. These findings provide valuable evidence supporting potential complement-based therapies targeting the C3a/C3aR/ERK/PANoptosis pathway in DCM treatment.
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Zhang et al. (2026) studied Diabetic cardiomyopathy (STZ-induced mouse model and in vitro AC16 human cardiomyocytes). C3a receptor antagonist (SB290157) or novel C3 cleavage inhibitor (CP40-KK) vs. Untreated STZ-induced diabetic cardiomyopathy model was evaluated on Cardiac function, myocardial hypertrophy, and activation of the C3aR/ERK/PANoptosis pathway. C3aR antagonist SB290157 (30 mg/kg/d) and C3 inhibitor CP40-KK (2 mg/kg/d) for 8 weeks improved cardiac function, reduced hypertrophy, and inhibited PANoptosis in diabetic mice.
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