Dual-Function Lipid Mediator: Comprehensive Analysis of 13-HODE in Metabolism, Ferroptosis, and Cancer

Chapter One: Biosynthesis and Metabolic Regulation of 13-HODE

As an active lipid mediator derived from linoleic acid, 13-hydroxyoctadecadienoic acid (13-HODE) has a diverse biosynthetic pathway that directly determines its functional complexity. Under physiological conditions, 13-HODE is primarily generated through two distinct pathways: precisely regulated enzymatic synthesis and random non-enzymatic oxidation. The structural characteristics and biological functions of the resulting 13-HODE differ fundamentally between these two production methods.

1.1 Enzymatic Synthesis Pathway: Core Role of 15-Lipoxygenase-1

In mammalian cells, 15-lipoxygenase-1 (15-LOX-1/ALOX15) is the main enzyme catalyzing the conversion of linoleic acid to 13-HODE. This enzyme exhibits high expression levels in macrophages, endothelial cells, eosinophils, and neutrophils. Its catalytic process demonstrates significant regional selectivity and stereospecificity; it specifically recognizes the carbon atom at position thirteen on the linoleic acid molecule chain to generate a peroxide precursor—13-hydroperoxy-octadecadienoic acid (13-HPODE)—through precise oxidative reactions before rapidly converting into stable hydroxyl derivative 13-HODE under the action of reducing enzymes like glutathione peroxidase.

Notably, this enzymatic process almost exclusively produces the (S)-configured enantiomer known as 13(S)-HODE. This stereospecificity is crucial for its biological activity since different stereoisomers may activate entirely different signaling pathways. In certain physiological environments, the affinity of 15-LOX-1 for linoleic acid significantly exceeds that for arachidonic acid; this substrate preference directly determines the relative proportions of various lipid mediators within local microenvironments affecting cellular functional states.

1.2 Auxiliary Role of Cyclooxygenase Pathway

Although lipoxygenase pathways are primary routes for synthesizing 13-HODE, cyclooxygenases (COX-1 and COX-2) can also metabolize linoleic acid to produce it. As key enzymes in prostaglandin synthesis processes with relatively weaker metabolic capacity towards linoleic acid compared to lipoxygenases, the COX system provides potential molecular nodes facilitating cross-talk between prostaglandin signaling axes and lipoxygenase signaling axes during specific pathological conditions such as chronic inflammation or tumor microenvironments where COX pathways might become important supplementary sources for generating additional amounts of HODES influencing overall cellular lipid signal network balance.

1.3 Non-Enzymatic Generation: Biomarker for Oxidative Stress

In stark contrast to precisely regulated enzymatic reactions stands non-enzyme-mediated generation whereby excessive oxidative stress leads directly to increased levels produced via free radical attacks on polyunsaturated fatty acids causing nonspecific lipid peroxidation reactions without any dependence upon catalytic enzymes thereby lacking both regional selectivity & stereoselectivity yielding mixtures containing roughly equal amounts each corresponding isoform existing racemically either as (S)- or(R)-isomers respectively leading ultimately toward observable shifts seen among tissue fluids ratios which serve now effectively distinguishing origins thereof . Detection patterns noted among human advanced atherosclerotic plaques exhibiting nearly equimolar distributions closely resembling unity reflect breakdowns occurring within antioxidant systems indicative unchecked oxidant damages being suffered . Such transitions from enzymatically driven productions toward those arising out unregulated processes signify not merely biochemical alterations but fundamental shifts transitioning from physiologically controlled mechanisms unto pathological damage trajectories unfolding ahead .

**... [Content continues] ... **