Eriocitrin Attenuates Diabetic Cardiomyopathy by Regulating Copper Homeostasis and Cuproptosis-Associated Pathways via SIRT7/YAP/ATP7A Signalling.

Diabetic cardiomyopathy (DCM) is a major complication of diabetes mellitus, with limited therapeutic strategies available. Cuproptosis, a novel form of copper-dependent cell death, has been implicated in cardiac dysfunction but remains unexplored in DCM. Here, we investigated the effects of Eriocitrin, a natural flavonoid, on DCM and examined the potential involvement of copper homeostasis, cuproptosis-associated molecular alterations and SIRT7/YAP/ATP7A signalling. Using high-fat diet and streptozotocin-induced diabetic mice, along with high-glucose-treated cardiomyocytes, we demonstrated that Eriocitrin improved cardiac function, attenuated myocardial remodelling and corrected glucose and lipid metabolism. Mechanistically, Eriocitrin improved myocardial copper homeostasis by enhancing ATP7A and ATP7B expression and reducing copper accumulation and cuproptosis-associated molecular alterations. Loss of SIRT7 impaired these effects, suggesting that SIRT7-associated YAP/ATP7A signalling contributes to Eriocitrin-mediated cardioprotection. The therapeutic efficacy of Eriocitrin showed similar protective trends to tetrathiomolybdate, a copper chelator. These findings suggest that Eriocitrin alleviates experimental DCM in association with improved myocardial copper homeostasis and attenuation of cuproptosis-associated molecular alterations, with SIRT7-associated YAP/ATP7A signalling potentially contributing to these effects.