The process of Lipid Peroxidation:

Initiation: A highly reactive radical, such as a hydroxyl radical, extracts a hydrogen atom from a polyunsaturated fatty acid (PUFA) in a cell membrane. This creates a lipid radical.

Propagation: The lipid radical quickly reacts with oxygen to form a lipid peroxyl radical, which is also highly reactive. This new radical then steals a hydrogen atom from a neighboring fatty acid, creating a new lipid radical and a stable, but harmful, lipid hydroperoxide (LOOH). This step perpetuates the chain reaction, amplifying the damage.

Termination:

The reaction continues until the radicals combine with each other or are neutralized by an antioxidant. The antioxidant defense network Tocopherol, ascorbate, and glutathione work synergistically to interrupt the chain reaction of lipid peroxidation and neutralize the resulting hydroperoxides.

The antioxidant defense network:

Tocopherol, ascorbate, and glutathione work synergistically to interrupt the chain reaction of lipid peroxidation and neutralize the resulting hydroperoxides.

Tocopherol (Vitamin E) Action:

As a lipid-soluble antioxidant, alpha-tocopherol (the most active form of vitamin E) is the first line of defense within the fatty cell membrane. It breaks the chain reaction by donating a hydrogen atom to the damaging lipid peroxyl radical (LOO), converting it to a stable lipid hydroperoxide (LOOH). In this process, the tocopherol is oxidized, becoming a less reactive tocopheroxyl radical.

Ascorbate (Vitamin C)
Action:

This water-soluble antioxidant operates in the watery parts of the cell (the cytosol). It regenerates the active form of tocopherol by donating an electron to the tocopheroxyl radical at the lipid-water interface of the cell membrane. Ascorbate is converted to an ascorbyl radical in the process.

Glutathione

This tripeptide plays a dual role in neutralizing lipid peroxidation.

Reducing hydroperoxides:

The selenium-dependent enzyme glutathione peroxidase (GPx4) uses two molecules of reduced glutathione (GSH) to convert the toxic lipid hydroperoxides (LOOH) into less harmful lipid hydroxides (LOH), effectively detoxifying the primary product of the reaction. This reaction oxidizes glutathione, producing glutathione disulfide (GSSG).

Regenerating ascorbate:

Glutathione also helps recycle ascorbate. When ascorbate is oxidized to a radical or to dehydroascorbate, glutathione is used as a reducing agent to regenerate it, often with the help of the enzyme dehydroascorbate reductase. An enzyme called glutathione reductase then recycles GSSG back to GSH, using NADPH as an electron source, completing the cycle.

Summary of the antioxidant cycle

The interplay of these three molecules can be summarized as a relay-like regeneration process:

Tocopherol (in membranes) neutralizes peroxyl radicals, forming tocopheroxyl radicals.

Ascorbate (in cytosol) regenerates tocopherol, becoming oxidized to an ascorbyl radical.

Glutathione (in cytosol) can regenerate ascorbate and, via the enzyme GPx4, detoxify the lipid hydroperoxides created by tocopherol's action.

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Urate (the mono-anion of uric acid, which is predominant at physiological pH 7.4) acts as a potent electron donor and the primary water-soluble antioxidant in human plasma. Its antioxidant effect includes the ability to regenerate other antioxidants, most notably ascorbate (Vitamin C).
Mechanism as an Electron Donor
Urate functions by donating a single electron to neutralize various reactive oxygen species (ROS) and free radicals. This reaction quenches the harmful radical species and converts them into more stable, less reactive products.
The donation of one electron converts urate into a relatively stable, short-lived urate radical (also known as the urate anion free radical, or a dehydrourate intermediate).

Antioxidant Regeneration
The key to urate's role in regenerating other antioxidants lies in the fate of this urate radical. In a sequential process, the urate radical can be reduced back to urate by other available antioxidants, such as ascorbate or glutathione (GSH). This "sacrificial" action effectively stabilizes and regenerates the other antioxidant (ascorbate in particular), allowing it to continue its protective role, while urate cycles between its reduced and oxidized forms.
Urate also helps regenerate or protect ascorbate by chelating transition metal ions (like iron and copper). These metal ions typically catalyze the oxidation of ascorbate, so by binding them, urate indirectly stabilizes the ascorbate concentration in the plasma.
pH Dependence
The antioxidant activity of urate is highly dependent on pH:
Physiological pH (around 7.4): Uric acid exists predominantly as the mono-anion, urate. In this ionized form, it is highly soluble and an efficient electron donor, accounting for a significant portion (up to two-thirds) of the total plasma antioxidant capacity.
Lower pH: At lower, more acidic pH levels (below its pKa of 5.4), uric acid is less ionized and loses much of its antioxidant ability.
In essence, urate's ability to act as an electron donor and regenerate other antioxidants is a key protective mechanism against systemic oxidative stress, particularly effective at the neutral pH found in human plasma.