Ray wrote extensively about the toxicity of polyunsaturated fatty acids (PUFA) , particularly their propensity to undergo lipid peroxidation and generate toxic breakdown products. He emphasized that PUFAs suppress oxidative metabolism, interfere with mitochondrial function, and promote inflammation and fibrosis. I have discussed specific arachidonic acid metabolites — particularly 4-hydroxynonenal (4-HNE) and 20-HETE (20-hydroxyeicosatetraenoic acid) — showing how they directly impair mitochondrial electron transport, increase oxidative stress, and inhibit ATP synthesis. The study below, published in Nature Communications, uses multiomics analysis of 766 patients with advanced cirrhosis to reveal that 20-HETE is a key driver of disease progression and mortality. The researchers found that 20-HETE induces mitochondrial oxidative stress and impairs mitochondrial respiration via a GPR75-Akt signaling pathway. This is a direct experimental validation of the bioenergetic view that Ray and I have separately articulated for decades.
As the study below demonstrates, researchers integrated multiomics data from 766 patients with acutely decompensated cirrhosis and identified a network connecting mitochondrial dysfunction with the accumulation of the lipid mediator 20-HETE (20-hydroxyeicosatetraenoic acid) , a metabolite of arachidonic acid (a PUFA). Among 291 features analyzed, 22 were linked to ACLF (acute-on-chronic liver failure) development and 16 to mortality. In vitro validation on human peripheral leukocytes showed that 20-HETE induces mitochondrial oxidative stress and impairs mitochondrial respiration via a GPR75-Akt signaling pathway. The network features acted as early predictors of outcomes, validated in an independent cohort of 580 patients.
This finding directly validates the bioenergetic view of liver disease:
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Arachidonic acid metabolite 20-HETE is directly toxic to mitochondria. I have written extensively about how arachidonic acid-derived eicosanoids and their downstream products inhibit complex I and complex III of the electron transport chain, leading to decreased ATP and increased ROS. This study confirms that 20-HETE impairs mitochondrial respiration and induces oxidative stress.
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Ray correctly identified PUFA as metabolic poisons. He wrote that PUFAs suppress metabolic rate, increase estrogen, and promote fibrosis. This study shows that a specific metabolite of arachidonic acid (20-HETE) drives mitochondrial dysfunction and organ failure.
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The liver is the primary metabolic organ. Cirrhosis is not just “scarring”; it is a collapse of metabolic function driven by mitochondrial failure. By inhibiting ATP synthesis, 20-HETE prevents hepatocytes from performing basic functions.
The study does not provide specific human-equivalent doses, as it was an observational multiomics study. However, the practical implications are clear: reduce PUFA intake to near-zero to lower the production of arachidonic acid and its toxic metabolite 20-HETE. This means eliminating seed oils (soybean, corn, canola, sunflower, safflower), nuts, seeds, fatty fish, and grain-fed animal fats. Replace them with stable saturated fats (coconut oil, butter, tallow) that do not undergo peroxidation. Additionally, vitamin E (mixed tocopherols) is the primary chain-breaking antioxidant that stops lipid peroxidation — a point Ray emphasized repeatedly.
https://www.nature.com/articles/s41467-026-73386-5
Blood Multiomics Uncover Lipid-Mitochondria Link in Cirrhosis
“…Among 291 features, 22 are linked to ACLF development and 16 to mortality. These features constitute a network connecting mitochondrial dysfunction with the accumulation of the lipid mediator 20-hydroxyeicosatetraenoic acid (20-HETE) .”
“…In vitro validation of this network in human peripheral leukocytes shows that 20-HETE induces mitochondrial oxidative stress and impairs mitochondrial respiration via a GPR75-Akt signaling pathway.”
“…Network features also act as early predictors of AD outcomes, a finding validated in an independent cohort of 580 patients.”
“…Here, we show a strong link between dysregulated immunomodulatory lipid mediators and mitochondrial dysfunction driving ACLF development and mortality risk in advanced cirrhosis.”
“…Exposure to dysregulated lipid mediators [20-HETE] prompted mitochondrial membrane depolarization, increased reactive oxygen species production, and impaired ATP synthesis .”
