Sphingolipid Metabolism and Signalling Pathways in Heart Failure: From Molecular Mechanism to Therapeutic Potential

Meng Zhao,1– 3 Rutao Bian,2 Xuegong Xu,2 Junpeng Zhang,2 Li Zhang,2 Yi Zheng2 1The First Clinical Medical College of Henan University of Chinese Medicine, Zhengzhou, Henan Province, People’s Republic of China; 2Department of Cardiology, Zhengzhou Hospital of Traditional Chinese Medicine, Zhengzhou, Henan Province, People’s Republic of China; 3Joint Formula and Syndrome Research Laboratory of Guangzhou University of Chinese Medicine & Zhengzhou Hospital of Chinese Medicine, Zhengzhou, Henan Province, People’s Republic of ChinaCorrespondence: Xuegong Xu; Junpeng Zhang, Zhengzhou Hospital of Traditional Chinese Medicine, Zhengzhou, Henan Province, People’s Republic of China, Email [email protected]; [email protected]: Sphingolipids are essential components of cell membranes and lipoproteins. They are synthesized de novo in the endoplasmic reticulum and subsequently undergo various enzymatic modifications in different organelles, giving rise to a diverse range of biologically active compounds. These molecules play a critical role in regulating cell growth, senescence, migration, apoptosis, and signaling. In recent years, the sphingolipid metabolic pathway has been recognized as a key factor in heart failure (HF) pathophysiology. Abnormal levels of sphingolipid metabolites, such as ceramide (Cer) and sphingomyelin (SM), contribute to oxidative stress and inflammatory responses, ultimately promoting cardiomyocyte apoptosis. Conversely, sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P) regulate vascular function and influence cardiac remodeling. Additionally, enzymes such as diacylglycerol acyltransferase 1 (DGAT1) and sphingosine-1-phosphate lyase 1 (SGPL1) modulate cardiac lipid metabolism. Given their role in HF progression, monitoring sphingolipid alterations offers potential as valuable biomarkers for assessing disease severity, prognosis, and diagnosis. Given the complexity of sphingolipid metabolism and its involvement in diverse regulatory biological processes, a comprehensive understanding of its roles at both the cellular and organismal levels in physiopathology remains incomplete. Therefore, this review aims to explore the physiological functions, regulatory mechanisms, and therapeutic potential of sphingolipid metabolism. It will summarize the specific molecular mechanisms driving key pathological processes in HF, including ventricular remodeling, myocardial fibrosis, vascular dysfunction, and metabolic disorders. Finally, the review will highlight targeted sphingolipid metabolites as potential therapeutic strategies, offering new insights into HF diagnosis and treatment, with the goal of advancing adjunctive clinical therapies.Keywords: sphingolipids, ceramide, cardiovascular disease, heart failure, mechanisms