Emerging role of 7-Ketocholesterol and hydroxylated 7-Ketocholesterol in the pathophysiology of disease

Cholesterol oxidation at the C7 position is a hallmark of non-enzymatic lipid peroxidation. Reactive oxygen species initiate hydrogen abstraction at the allylic C7 position of cholesterol, leading to the formation of 7-hydroperoxides, which subsequently decompose to yield 7-hydroxycholesterols and 7-ketocholesterol (7KC). Due to the relative chemical stability, 7KC accumulates preferentially and is commonly detected in biological samples, compared to more labile hydroperoxide intermediates. 7KC is known to induce oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum stress, leading to apoptosis, autophagy, or necrotic cell death depending on cell type and exposure conditions. In addition, 7KC promotes inflammatory pathways and membrane dysfunction, contributing to tissue damage in diseases associated with chronic oxidative stress. These mechanisms open opportunities for the development of targeted intervention strategies. Accumulation of 7KC also acts as a substrate that may undergo further metabolic or oxidative transformations. Importantly, cells possess enzymatic systems capable of introducing hydroxyl groups at the cholesterol side chain that 7KC can be further modified into double-substituted oxysterols (7-keto-25-hydroxycholesterol and 7-keto-27-hydroxycholesterol) combining a 7-keto moiety with side-chain hydroxylation. These metabolites of 7KC represent the dynamic interplay between oxidative damage and cellular sterol metabolic pathways. Elucidating their biological functions will be essential for a more comprehensive understanding of oxysterol biology in health and disease.