Regulation of phospholipid and lipid metabolism

Phospholipids play a crucial role in regulating lipid metabolism, with ongoing advancements in basic research providing theoretical support for their application in clinical interventions. The following is a detailed overview from basic research to clinical applications:

I. Basic Research

Rhythms of Phospholipid Synthesis Influence Metabolic Efficiency

The team led by Ye Cunqi from the Life Sciences Institute of Zhejiang University confirmed that eukaryotic cells exhibit an endogenous rhythm in phospholipid synthesis. Intracellular levels of different phospholipid molecules show precise temporal fluctuations: for example, phosphatidylcholine (PC) and phosphatidylethanolamine (PE) display a unique out-of-phase oscillation pattern, while the abundance oscillations of phosphatidylinositol (PI) and phosphatidylserine (PS) are significantly correlated with the chain length and unsaturation of fatty acid chains. This oscillation pattern highly matches the dynamic changes in membrane physical properties, suggesting that cells may optimize energy metabolism by accurately regulating the timing of lipid metabolism.

Phospholipid Metabolism Affects Immune Cell Function

The team led by Zhang Yi from the First Affiliated Hospital of Zhengzhou University found that tumor-infiltrating CD8⁺ T cells exhibit abnormal phospholipid metabolism, with significant reductions in phosphatidylcholine and phosphatidylethanolamine, and downregulated expression of phospholipid phosphatase 1. This leads to ferroptosis in T cells and impaired anti-tumor function. However, PD-1 monoclonal antibodies can enhance phospholipid phosphatase 1 expression, restore T cell phospholipid metabolism, and thereby strengthen T cell anti-tumor activity.

Sphingolipid Metabolism and Cardiac Regeneration

Professor Cao Nan’s team from the Zhongshan School of Medicine, Sun Yat-sen University, discovered that the sphingolipid metabolic pathway plays a key role in myocardial proliferation and cardiac regenerative repair. After myocardial injury, the level of the core sphingolipid metabolite sphingosine-1-phosphate (S1P) is upregulated. Its synthases, SphK1 and SphK2, exhibit opposite expression patterns during cardiac development and influence cardiac regeneration by regulating histone deacetylase complexes.

Hepatic Membrane Sphingolipid Metabolism and Liver Disease Progression

A research team from the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, found that dysregulation of hepatic membrane sphingolipid metabolism—particularly ceramide accumulation—is a core metabolic feature in the progression from simple fatty liver to metabolic dysfunction-associated steatohepatitis (MASH). Sphingomyelin phosphodiesterase 3 (SMPD3) is the main driver of this process: by altering the sphingomyelin-ceramide metabolic balance in caveolar regions, it promotes caveolae-dependent lipid uptake, drives hepatic lipid accumulation, and enhances the production and release of pro-inflammatory and pro-fibrotic extracellular vesicles from hepatocytes, exacerbating MASH progression.

II. Clinical Interventions

Treating Hyperlipidemia: Phospholipid soft capsules help regulate lipid metabolism. They can reduce low-density lipoprotein cholesterol levels by promoting hepatic metabolism and excretion of fats and inhibiting hepatic cholesterol synthesis, thereby improving hyperlipidemia symptoms.

Adjuvant Treatment of Fatty Liver: Phospholipids participate in lipoprotein synthesis; lipoproteins transport intrahepatic fats out of the liver, contributing to systemic lipid metabolism and supporting the adjuvant treatment of fatty liver.

Preventing and Treating Atherosclerosis: Phospholipids can lower serum cholesterol and total cholesterol levels, increase high-density lipoprotein, and reduce low-density lipoprotein, exerting preventive and therapeutic effects on atherosclerosis.

Improving Heart Diseases: Based on the relationship between sphingolipid metabolism and cardiac regeneration, intervening in sphingolipid metabolic targets is expected to promote cardiac regenerative repair after myocardial infarction, providing new strategies for treating heart diseases.

Enhancing Immunotherapy Efficacy: The team at the First Affiliated Hospital of Zhengzhou University is screening phospholipid phosphatase 1-targeted agonists. It is anticipated that these agonists will restore T cell phospholipid metabolism by enhancing phospholipid phosphatase 1 function, inhibit T cell ferroptosis, and thereby strengthen the anti-tumor function of T cells in immunotherapy.