The article by Yusuf A. Hannun and Lina M. Obeid provides an extensive overview of the complex and multifaceted roles of bioactive sphingolipids in physiology and disease. Sphingolipids, a class of eukaryotic lipids, have been increasingly recognized for their critical functions in various cellular processes and their links to human diseases. The authors highlight the recent advancements in understanding the biochemical and molecular mechanisms underlying sphingolipid metabolism, including the regulation of key enzymes and the study of lipid-protein interactions. Key points covered in the article include: 1. **Bioactive Lipids and Sphingolipids**: The concept of bioactive lipids, particularly sphingolipids, has evolved over several decades, with significant progress in understanding their roles in cell signaling and regulatory circuits. 2. **Sphingolipid Metabolism**: The article details the complex metabolic pathways of sphingolipids, involving around 40 enzymes in mammals, and the regulation of these pathways by various stimuli and agents. 3. **Regulatory Mechanisms**: Detailed discussions on the regulatory inputs and mechanisms of key enzymes involved in sphingolipid synthesis and catabolism, such as serine palmitoyltransferase (SPT), neutral sphingomyelinase 2 (nSMase2), and acid sphingomyelinase (aSMase). 4. **Therapeutic Targeting**: The article explores the potential of targeting sphingolipid pathways for therapeutic interventions, including the use of analogues of bioactive sphingolipids and inhibitors of specific enzymes. 5. **Cellular Functions**: The roles of sphingolipids in various cellular processes, such as cell growth, cell death, inflammation, and immune responses, are discussed, with a focus on recent studies using model organisms and advanced technologies. 6. **Implications in Disease**: The article examines the implications of altered sphingolipid metabolism in diseases such as cancer, diabetes, and cardiovascular disorders, highlighting the potential of sphingolipid levels and metabolic enzyme activity as biomarkers. Overall, the article underscores the importance of sphingolipids in both physiological and pathological contexts, emphasizing the need for further research to fully understand their complex roles and develop effective therapeutic strategies.The article by Yusuf A. Hannun and Lina M. Obeid provides an extensive overview of the complex and multifaceted roles of bioactive sphingolipids in physiology and disease. Sphingolipids, a class of eukaryotic lipids, have been increasingly recognized for their critical functions in various cellular processes and their links to human diseases. The authors highlight the recent advancements in understanding the biochemical and molecular mechanisms underlying sphingolipid metabolism, including the regulation of key enzymes and the study of lipid-protein interactions. Key points covered in the article include: 1. **Bioactive Lipids and Sphingolipids**: The concept of bioactive lipids, particularly sphingolipids, has evolved over several decades, with significant progress in understanding their roles in cell signaling and regulatory circuits. 2. **Sphingolipid Metabolism**: The article details the complex metabolic pathways of sphingolipids, involving around 40 enzymes in mammals, and the regulation of these pathways by various stimuli and agents. 3. **Regulatory Mechanisms**: Detailed discussions on the regulatory inputs and mechanisms of key enzymes involved in sphingolipid synthesis and catabolism, such as serine palmitoyltransferase (SPT), neutral sphingomyelinase 2 (nSMase2), and acid sphingomyelinase (aSMase). 4. **Therapeutic Targeting**: The article explores the potential of targeting sphingolipid pathways for therapeutic interventions, including the use of analogues of bioactive sphingolipids and inhibitors of specific enzymes. 5. **Cellular Functions**: The roles of sphingolipids in various cellular processes, such as cell growth, cell death, inflammation, and immune responses, are discussed, with a focus on recent studies using model organisms and advanced technologies. 6. **Implications in Disease**: The article examines the implications of altered sphingolipid metabolism in diseases such as cancer, diabetes, and cardiovascular disorders, highlighting the potential of sphingolipid levels and metabolic enzyme activity as biomarkers. Overall, the article underscores the importance of sphingolipids in both physiological and pathological contexts, emphasizing the need for further research to fully understand their complex roles and develop effective therapeutic strategies.