Advances in Studying the Role of Sphingosine Kinase 1 in Cardiovascular Disease

Abstract

Sphingosine kinase 1 (SphK1) is a central regulator of sphingosine-1-phosphate (S1P) signaling and has been extensively implicated in cardiovascular physiology and disease. However, studies across diverse experimental models have reported apparently conflicting roles for SphK1, ranging from cardioprotective effects to the promotion of pathological remodeling. These discrepancies have complicated the interpretation of SphK1 function and hindered its translational targeting. In this review, we propose a unifying framework in which SphK1 operates as a context-dependent signaling node whose biological consequences are dictated by cell type, stress duration, and subcellular localization. We summarize current evidence showing that acute, tightly regulated activation of SphK1 in cardiomyocytes supports adaptive stress responses and cell survival, whereas sustained or dysregulated SphK1 signaling in non-myocyte populations, including fibroblasts and vascular cells, drives maladaptive processes such as fibrosis, vascular remodeling, and tissue stiffening. We further discuss the multi-layered regulatory mechanisms governing SphK1 signaling, encompassing transcriptional and post-transcriptional control, post-translational activation, and functional compartmentalization. Together, these regulatory layers determine whether elevated SphK1 expression is translated into protective or pathological S1P signaling outputs. By integrating these findings, we highlight cell-specific maladaptation as a conceptual paradigm that reconciles divergent observations in the literature. This perspective underscores the importance of spatial and temporal precision in SphK1 signaling and provides a framework for the development of more selective and cell-targeted therapeutic strategies in cardiovascular disease.