The endocannabinoidome (eCBome) is a complex lipid signaling network that integrates metabolic, immune, and neurobehavioral processes in response to environmental cues. Dietary lipids and gut microbiota have emerged as major modulators of its activity and signaling tone. Intake of specific fatty acids, including the monounsaturated oleic acid, the omega-6 polyunsaturated linoleic acid, and omega-3 polyunsaturated fatty acids, influences the eCBome not only by serving as structural precursors of bioactive lipid mediators, but also by altering the relative abundance of these mediators through changes in substrate availability, enzymatic competition, and receptor-mediated feedback loops. Concurrently, gut microbiota shape host eCBome signaling by regulating lipid metabolism, inflammatory tone, and intestinal barrier integrity, while eCBome mediators reciprocally modulate microbial composition and function. Dysregulation of this complex diet-microbiota-eCBome interplay has been implicated in the pathogenesis of metabolic disorders, chronic inflammation, and neuropsychiatric conditions. In this review, we critically examine the molecular mechanisms underlying the interactions between dietary lipid composition, gut microbial ecology, and eCBome signaling. We discuss the implications for human health and highlight emerging diet-based therapeutic strategies targeting this axis.
Cardiometabolic diseases (CMD) are a major global health threat. Given their multifactorial pathogenesis, understanding the interconnected mechanisms driving disease progression is essential. Ferroptosis, an iron-dependent form of regulated cell death characterized by iron accumulation, lipid peroxidation, and compromised antioxidant defenses, is emerging as a promising target for therapeutic intervention in CMD. Growing evidence underscores the intricate interplay among iron metabolism, redox homeostasis, and lipid metabolism in regulating ferroptosis and CMD. Notably, we propose the concept of an "iron paradox" as an integrative framework to synthesize these observations. Despite representing opposite systemic iron states, both iron deficiency and iron overload can converge on ferroptotic vulnerability by disrupting subcellular iron trafficking, mitochondrial function, lipid remodeling, and antioxidant defense. This framework emphasizes that ferroptosis risk in CMD is not primarily governed directly by absolute iron abundance, but more so the interaction between redox-active iron, PUFA-containing phospholipids and lipid peroxide detoxification systems. We then describe the molecular regulation of ferroptosis, with a focus on disruptions in iron and lipid homeostasis as drivers of lipid peroxidation. The contribution of these cellular changes to CMD pathophysiology is then described. Finally, we summarize preclinical evidence supporting ferroptosis-targeted interventions and outline future directions for translational research and therapeutic innovation.
The oxidation of cholesterol at the Δ5 double bond generates 5,6-epoxycholestanols (5,6-ECs), which exist as two diastereoisomers, 5,6α-EC and 5,6β-EC. These metabolites define a distinct branch of sterol metabolism that integrates redox chemistry with receptor signaling. Once considered artefactual autoxidation products, 5,6-ECs are now recognized as regulated intermediates arising from enzymatic, oxidative, and environmental sources, and yielding structurally and functionally diverse metabolites, here termed the epoxycholestanoid (EChA) family. Cholesterol-5,6-epoxide hydrolase (ChEH; EBP/DHCR7 complex) converts 5,6-ECs into cholestane-3β,5α,6β-triol (CT), which is subsequently oxidized by 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) to form 6-oxocholestan-3β,5α-diol (OCDO), a glucocorticoid receptor (GR)-biased agonist that promotes tumor growth. In parallel, 5,6α-EC undergoes stereoselective conjugation with histamine to generate dendrogenin A (DDA), an endogenous liver X receptor β (LXRβ)-biased agonist that displays tumor suppressive and neurostimulating functions. These opposing OCDO-GR and DDA-LXRβ pathways are embedded in enzyme-coupled feedback loops that link oxidative stress, sterol metabolism, and transcriptional control. This review integrates lipidomics, enzymology, receptor pharmacology, and disease biology to define the EChA family as a conserved redox-responsive signaling network at the interface of cholesterol metabolism, inflammation, ageing, and disease, offering new opportunities for biomarker discovery and therapeutic intervention.
