Advancements in understanding the role of oxylipins in liver injury and liver failure

Abstract
End‑stage liver disease (ESLD), including decompensated cirrhosis and acute‑on‑chronic liver failure, is driven by persistent inflammation that fails to resolve. Bioactive oxylipins – lipid mediators derived from polyunsaturated fatty acids – orchestrate both pro‑inflammatory and pro‑resolving responses. This review synthesizes current knowledge on oxylipin biosynthesis, their immunomodulatory roles, and their emerging potential as biomarkers and therapeutic targets in ESLD. Dysregulated oxylipin profiles (e.g., elevated PGE₂, LTB₄, 20‑HETE, and reduced resolvins) correlate with disease severity, organ dysfunction, and mortality. Mechanistically, oxylipins regulate hepatic macrophages, stellate cells, and immune crosstalk. Therapeutic strategies include COX‑2/5‑LOX inhibition, soluble epoxide hydrolase inhibition, administration of pro‑resolving mediators (lipoxins, resolvins), and gut‑microbiota modulation. Despite challenges in patient heterogeneity and lipidomic analysis, oxylipin‑based interventions hold promise for improving ESLD outcomes.

Introduction
ESLD results from chronic liver injury and is characterized by systemic inflammation, immune dysfunction, and high mortality. Failure to resolve inflammation – rather than excessive pro‑inflammatory signaling alone – is a key driver. Bioactive oxylipins, oxygenated metabolites of n‑6 and n‑3 polyunsaturated fatty acids (PUFAs), act as pivotal regulators of inflammation and its resolution. This review examines oxylipin sources, their roles in liver injury, and their therapeutic potential.

Types and Sources of Bioactive Oxylipins
Oxylipins are generated from arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) via three enzymatic pathways: cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP450).

• COX pathway: produces prostaglandins (e.g., PGE₂) and thromboxanes (TXA₂).

• LOX pathway: yields leukotrienes (e.g., LTB₄), hydroxyeicosatetraenoic acids (HETEs), and specialized pro‑resolving mediators (SPMs: lipoxins, resolvins, protectins, maresins).

• CYP450 pathway: generates epoxyeicosatrienoic acids (EETs) and 20‑HETE.
  Cells involved include macrophages, neutrophils, endothelial cells, and hepatocytes, with transcellular biosynthesis being critical for SPM production.

Modulatory Roles of Oxylipins in Inflammatory Responses
Pro‑inflammatory oxylipins (PGE₂, LTB₄, TXA₂, 20‑HETE) amplify cytokine release, recruit leukocytes, promote vasoconstriction, and activate hepatic stellate cells (HSCs), driving fibrosis. In contrast, SPMs (LXA₄, RvD1, RvE1, MaR1) actively resolve inflammation by enhancing efferocytosis, promoting M2 macrophage polarization, and restoring tissue homeostasis. Their actions are mediated by specific G‑protein‑coupled receptors (e.g., EP receptors for PGE₂, BLT1 for LTB₄, ALXR/FPR2 for SPMs).

Oxylipins in Liver Injury and Failure – Biomarker Evidence
Clinical lipidomic studies (CANONIC cohort, HBV‑ACLF cohorts, ALD/NAFLD) reveal distinct oxylipin signatures:

• Decompensated cirrhosis/ACLF: elevated LTE₄, 12‑HHT, 20‑HETE, PGE₂, LTB₄, and various HETEs; reduced SPMs (RvD1, RvE1, MaR1) in plasma and extracellular vesicles.

• HBV‑related ACLF: increased pro‑inflammatory n‑6 derivatives and compensatory rises in EPA/DHA metabolites.

• NAFLD/NASH: elevated PGF₂α and altered 13‑HODE.
  These oxylipins correlate with disease severity, short‑term mortality, and organ failure, highlighting their diagnostic and prognostic potential (Table 1 in original).

Mechanisms of Oxylipins in Liver Injury

• COX‑2/PGE₂: promotes inflammation and immunosuppression in cirrhosis but also has hepatoprotective roles (e.g., inhibiting HSC collagen synthesis). PGE₂ mediates monocyte dysfunction via EP4.

• CYP450/20‑HETE: the most abundant hepatic oxylipin; promotes fibrosis via TGF‑β/Smad3 and activates GPR75, linking to portal hypertension.

• LOX pathways: 12‑HETE aggravates ischemia‑reperfusion injury and HCC recurrence; LTB₄/LTC₄ activate HSCs; LXA₄ and SPMs counteract these effects.

• Dual roles: PGE₂ can both worsen and limit injury depending on receptor subtype, timing, and cellular context.

Cellular Sources and Immune Crosstalk
Kupffer cells (liver macrophages) are major producers of COX/LOX‑derived oxylipins. Under injury, they shift to an M1 phenotype, releasing pro‑inflammatory eicosanoids. SPMs (RvD1, MaR1) promote M2 polarization and inflammation resolution. Other cells (HSCs, T cells, neutrophils) also contribute; for instance, senescent HSCs produce PGE₂ that suppresses antitumor immunity, while TXA₂ inhibits T‑cell function via ARHGEF1.

Gut Microbiota and Oxylipin Metabolism
Gut dysbiosis, a hallmark of ESLD, alters host oxylipin profiles. For example, Bacteroides fragilis downregulates pro‑inflammatory oxylipins; antibiotics and obesogenic diets increase LTB₄. Microbial products (lipoteichoic acid) can activate COX‑2, and bacterial lysates enhance TXB₂ secretion from Kupffer cells. The microbiota‑oxylipin‑liver axis remains underexplored but represents a promising therapeutic target.

Therapeutic Strategies Targeting Oxylipins

• Enzyme inhibitors: COX‑2 inhibitors (celecoxib, meloxicam) reduce fibrosis and decompensation events; 5‑LOX inhibitor zileuton attenuates liver injury and NAFLD progression.

• Soluble epoxide hydrolase (sEH) inhibitors: increase protective EET levels, reducing steatosis and fibrosis.

• SPM administration: LXA₄ and resolvins (RvD1, RvE1) alleviate hepatitis and promote resolution.

• Albumin infusion: binds PGE₂, reducing its immunosuppressive effects.

• Dietary ω‑3 PUFA: provides precursors for SPMs.
  Clinical data support safety of selective COX‑2 inhibitors in cirrhotic patients (no renal toxicity). Combination strategies (e.g., ω‑3 + sEH inhibitor) show preclinical promise.

Future Prospects
Challenges include patient heterogeneity (etiology, comorbidities), need for multi‑cohort validation, limited mechanistic studies beyond macrophages, and technical limitations of lipidomics (non‑targeted vs. targeted). Future directions:

• Detailed clinical subtyping to link oxylipin profiles with specific insults.

• Expand immune cell analyses (T cells, granulocytes).

• Investigate gut microbiota‑oxylipin interactions and their causal role.

• Develop better lipid quantification and in vivo tracking methods.

• Translate preclinical findings into biomarker‑guided, personalized therapies.

Conclusions
Oxylipins are central regulators of inflammation and resolution in ESLD. Their dysregulated profiles serve as diagnostic and prognostic biomarkers, and they offer multiple therapeutic intervention points – from enzyme inhibition to SPM supplementation and microbiome modulation. Overcoming current limitations in patient stratification and analytical methods will be key to translating oxylipin‑based strategies into clinical practice for decompensated cirrhosis and acute‑on‑chronic liver failure.

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https://www.xiahepublishing.com/2310-8819/JCTH-2025-00502

The study was recently published in the Journal of Clinical and Translational Hepatology.

The Journal of Clinical and Translational Hepatology (JCTH) is owned by the Second Affiliated Hospital of Chongqing Medical University and published by XIA & HE Publishing Inc. JCTH publishes high quality, peer reviewed studies in the translational and clinical human health sciences of liver diseases. JCTH has established high standards for publication of original research, which are characterized by a study’s novelty, quality, and ethical conduct in the scientific process as well as in the communication of the research findings. Each issue includes articles by leading authorities on topics in hepatology that are germane to the most current challenges in the field. Special features include reports on the latest advances in drug development and technology that are relevant to liver diseases. Regular features of JCTH also include editorials, correspondences and invited commentaries on rapidly progressing areas in hepatology. All articles published by JCTH, both solicited and unsolicited, must pass our rigorous peer review process.

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