Utilization of lipids as energy substrates after birth causes cardiomyocyte (CM) cell-cycle arrest and loss of regenerative capacity in mammalian hearts. Beyond energy provision, proper management of lipid composition is crucial for cellular and organismal health, but its role in heart regeneration remains unclear. Here, we demonstrate widespread sphingolipid metabolism remodeling in neonatal hearts after injury and find that SphK1 and SphK2, isoenzymes producing the same sphingolipid metabolite sphingosine-1-phosphate (S1P), differently regulate cardiac regeneration. SphK2 is downregulated during heart development and determines CM proliferation via nuclear S1P-dependent modulation of histone acetylation. Reactivation of SphK2 induces adult CM cell-cycle re-entry and cytokinesis, thereby enhancing regeneration. Conversely, SphK1 is upregulated during development and promotes fibrosis through an S1P autocrine mechanism in cardiac fibroblasts. By fine-tuning the activity of each SphK isoform, we develop a therapy that simultaneously promotes myocardial repair and restricts fibrotic scarring to regenerate the infarcted adult hearts.

出生后利用脂质作为能量底物会导致哺乳动物心脏心肌细胞（CM）细胞周期停滞和再生能力丧失。除了提供能量之外，脂质成分的适当管理对于细胞和有机体健康也至关重要，但其在心脏再生中的作用仍不清楚。在这里，我们证明了损伤后新生儿心脏中广泛的鞘脂代谢重塑，并发现 SphK1 和 SphK2 这两种同工酶产生相同的鞘脂代谢物 1-磷酸鞘氨醇 (S1P)，以不同的方式调节心脏再生。 SphK2 在心脏发育过程中下调，并通过核 S1P 依赖性组蛋白乙酰化调节来决定 CM 增殖。 SphK2 的重新激活会诱导成体 CM 细胞周期重新进入和胞质分裂，从而增强再生。相反，SphK1 在发育过程中上调，并通过心脏成纤维细胞中的 S1P 自分泌机制促进纤维化。通过微调每种 SphK 同工型的活性，我们开发了一种疗法，可以同时促进心肌修复并限制纤维化疤痕形成，从而使梗塞的成人心脏再生。