The role of phospholipids in antioxidant stress

As the core component of biological membranes, phospholipids not only maintain the integrity of membrane structures but also play a key role in cellular defense against oxidative damage by participating in antioxidant stress responses and regulating related signaling pathways. Their mechanisms of action can be analyzed from two aspects: direct antioxidant effects and signaling pathway regulation.

I. Direct Antioxidant Stress Effects of Phospholipids

The structural characteristics of phospholipid molecules enable them to directly scavenge reactive oxygen species (ROS) or reduce oxidative stress-induced cellular damage:

Physical barrier function of membrane structures: Phospholipids (such as phosphatidylcholine and phosphatidylethanolamine) form a bilayer membrane structure, isolating intracellular sensitive components from the external oxidative environment. Among them, phospholipids containing polyunsaturated fatty acids (PUFAs), such as phosphatidylinositol, are susceptible to oxidation by ROS, but this "sacrificial" oxidation can protect membrane proteins and DNA from attack; while phospholipids containing saturated or monounsaturated fatty acids enhance the antioxidant stability of the membrane.

Antioxidant function of phospholipid derivatives: Derivatives produced by phospholipid metabolism, such as lysophospholipids and phosphatidylinositol, can directly scavenge free radicals (e.g., hydroxyl radicals, superoxide anions) or inhibit Fenton reaction-mediated ROS generation by chelating transition metal ions such as iron and copper. For example, phosphatidylserine can bind to metal ions through the amino group in its polar head, reducing the intensity of oxidative stress.

II. Phospholipid Regulation of Antioxidant Stress via Signaling Pathways

As precursors or messengers of signaling molecules, phospholipids enhance cellular antioxidant capacity by activating downstream pathways, mainly involving the following mechanisms:

Phosphatidylinositol 3-kinase (PI3K/Akt) pathway

Phosphatidylinositol (PI) is converted to phosphatidylinositol-3,4,5-trisphosphate (PIP3) under the action of kinases, which activates Akt kinase and further regulates downstream antioxidant-related molecules:

Activating nuclear factor E2-related factor 2 (Nrf2): Akt phosphorylates Keap1, the inhibitory protein of Nrf2, allowing Nrf2 to dissociate and enter the nucleus, initiating the expression of antioxidant genes such as heme oxygenase-1 (HO-1) and glutathione peroxidase (GPx), thereby enhancing the cell's ability to scavenge ROS.

Inhibiting pro-apoptotic signals: Akt phosphorylates molecules such as Bad and Caspase-9, reducing oxidative stress-induced cell apoptosis and maintaining cellular homeostasis.

Phospholipase C (PLC)/protein kinase C (PKC) pathway

Phospholipase C catalyzes the hydrolysis of phosphatidylinositol-4,5-bisphosphate (PIP2) into inositol trisphosphate (IP3) and diacylglycerol (DAG). DAG activates PKC, triggering an antioxidant cascade reaction:

PKC can directly phosphorylate Nrf2, promoting its nuclear translocation; it also upregulates the activity of antioxidant enzymes (such as superoxide dismutase, SOD), enhancing cellular antioxidant defense.

Under oxidative stress, PKC can activate members of the MAPK family (e.g., ERK1/2), further amplifying antioxidant signals and reducing the accumulation of lipid peroxidation products (such as malondialdehyde, MDA).

Sphingomyelin metabolism-related pathways

Sphingomyelin is converted to ceramide by sphingomyelinase, which participates in stress responses by regulating intracellular redox balance:

Low concentrations of ceramide can activate antioxidant pathways (such as Nrf2), enhancing cellular adaptation to oxidative damage; however, high concentrations of ceramide induce mitochondrial dysfunction, promoting excessive ROS production and exacerbating oxidative stress. This dual role is closely related to cell type and stress intensity.

Phosphatidic acid (PA)-mediated signaling pathways

As an important second messenger, phosphatidic acid can regulate the synthesis of antioxidant proteins by activating the mammalian target of rapamycin (mTOR) pathway:

After mTOR activation, it promotes the phosphorylation of ribosomal protein S6 kinase (S6K), accelerating the translation of antioxidant enzymes (such as catalase, CAT) and improving the cell's ability to scavenge H₂O₂; it also inhibits excessive activation of autophagy, avoiding autophagic cell death caused by oxidative stress.

III. Pathological and Physiological Significance

The regulatory mechanisms of phospholipids in antioxidant stress are of great significance in various diseases:

In neurodegenerative diseases, disordered phospholipid metabolism in the brain impairs the activation of the Nrf2 pathway, leading to ROS accumulation and neuronal damage. Supplementation with specific phospholipids (such as phosphatidylserine) can partially restore antioxidant capacity.

In cardiovascular diseases, abnormal activation of phospholipase A2 in vascular endothelial cells triggers lipid peroxidation. Regulating the PI3K/Akt pathway can enhance the antioxidant defense of endothelial cells and alleviate atherosclerosis.

Phospholipids form a multi-layered defense network against cellular oxidative stress through directly scavenging ROS and regulating pathways such as PI3K/Akt and PLC/PKC. The analysis of their mechanisms provides new targets for the prevention and treatment of oxidative stress-related diseases.