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I will introduce novel mechanisms of mammalian cardiac regeneration and repair following injury, a major challenge in current biomedical research using mouse, rats and pigs’ models (Tzahor and Poss, Science 2017, Tzahor and Dimmeler, Science 2022). We focused on the role of NRG1-ErbB2 signaling pathway in cardiac regeneration (D’Uva NCB 2015; Aharonov NCB 2020, Shakked NCVR 2023). We have revealed that the proteoglycan Agrin can serve as an inducer of mammalian heart regeneration, with a great therapeutic potential for the treatment of ischemic heart disease (Bassat et al., Nature 2017; Sarig et al., Circulation 2019; Baehr et al., Circulation 2020; Zhang NCVR 2024). I will discuss regenerative senescence in cardiac injuries (Zhang NCVR 2024) and our efforts to repurpose Copaxone, a prescribed drug for multiple sclerosis, for the treatment of heart disease patients (Aviel, NCVR 2024) and a novel concept related to cardiac fibrosis (Miyara Cell Syst 2025).