Zheng Lixia, Chen Yuanyuan, Xiong Jing-Wei
Beijing Key Laboratory of Cardiometabolic Molecular Medicine, and, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, 100871, China.
School of Basic Medical Sciences, The Second Affiliated Hospital, Institute of Biomedical Innovation, and The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, Jiangxi Medical College, Nanchang University, Nanchang, 330031, China.
Cell Regen. 2025 Sep 28;14(1):40. doi: 10.1186/s13619-025-00257-7.
The adult mammalian heart exhibits minimal regenerative capacity due to postnatal cell-cycle arrest of cardiomyocytes. In contrast, lower vertebrates such as zebrafish retain the ability to fully regenerate heart after injury. This capacity is driven not only by transcriptional and structural plasticity but also by metabolic reprogramming that supports cardiomyocyte proliferation. Adult mammalian cardiomyocytes lack both features, remaining largely refractory to regenerative cues. These limitations have prompted efforts to identify extrinsic genetic and metabolic regulators capable of reactivating proliferative competence in adult cardiomyocytes. In this review, we highlight recent advances in the molecular and metabolic control of cardiomyocyte cell-cycle reentry, focusing on strategies that modulate dedifferentiation, proliferation, and redifferentiation as well as metabolic state transitions. We also examine emerging translational approaches in swine models, which more closely recapitulate human cardiac physiology than rodents. Together, these insights provide a roadmap for unlocking endogenous regenerative pathways and identify key challenges in translating these findings into therapies for heart failure.
成年哺乳动物的心脏由于心肌细胞出生后细胞周期停滞，再生能力极小。相比之下，斑马鱼等低等脊椎动物在心脏受伤后仍保留完全再生的能力。这种能力不仅由转录和结构可塑性驱动，还由支持心肌细胞增殖的代谢重编程驱动。成年哺乳动物心肌细胞缺乏这两个特征，对再生信号基本上仍无反应。这些限制促使人们努力寻找能够重新激活成年心肌细胞增殖能力的外在遗传和代谢调节因子。在这篇综述中，我们重点介绍了心肌细胞细胞周期重新进入的分子和代谢控制方面的最新进展，重点关注调节去分化、增殖和再分化以及代谢状态转变的策略。我们还研究了猪模型中新兴的转化方法，猪模型比啮齿动物更能模拟人类心脏生理学。总之，这些见解为开启内源性再生途径提供了路线图，并确定了将这些发现转化为心力衰竭治疗方法的关键挑战。
