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2000
Volume 26, Issue 1
  • ISSN: 1871-5303
  • E-ISSN: 2212-3873
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Abstract

Background

Hepatic Ischemia-Reperfusion Injury (IRI) is a critical complication in liver transplantation and resection, driven by oxidative stress and sterile inflammation mediated by damage-associated molecular patterns (DAMPs). Current therapeutic challenges arise from interconnected cell death pathways and redundant inflammatory mechanisms.

Objective

This review synthesizes mechanistic insights into DAMP signaling and regulated cell death modalities in IRI, aiming to identify translational gaps and propose precision-targeted therapies.

Methods

A literature search in PubMed using keywords “IRI,” “DAMPs,” and cell death modes was conducted without date restrictions. Peer-reviewed studies on human/animal models were included, with qualitative synthesis of DAMP-cell death interactions.

Results

During ischemia, mitochondrial dysfunction releases HMGB1, ATP, and mtDNA, activating Kupffer cell TLR4/RAGE and cGAS-STING pathways, triggering NLRP3 inflammasome- driven cytokine storms. Reperfusion amplifies ROS bursts, lipid peroxidation, and iron overload, creating a self-sustaining cycle of damage. Cell death modalities exhibit spatiotemporal specificity: hepatocyte ferroptosis dominates early injury, while macrophage pyroptosis and necroptosis predominate in steatotic livers during late phases. HMGB1 lactylation and mtDNA-cGAS signaling emerge as key regulators. Machine perfusion (, hypothermic oxygenated perfusion) reduces biliary complications mitochondrial resuscitation, outperforming conventional drug-based therapies.

Conclusion

Current single-pathway targeting shows limited efficacy due to IRI’s complexity. Future strategies should integrate temporal targeting (ferroptosis inhibitors pre-reperfusion; pyroptosis blockers post-reperfusion), DAMP-neutralizing agents (anti-HMGB1 antibodies), and precision preservation combining multi-omics biomarkers with pharmacological preconditioning. Addressing metabolic vulnerabilities in fatty livers and refining cell death-specific interventions are critical for bridging translational gaps.

© 2026 The Author(s). Published by Bentham Science Publishers.
This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode
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/content/journals/emiddt/10.2174/0118715303401342250514102731
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Sterile Inflammation and Cell Death Pathways in Liver Ischemia-Reperfusion Injury: A Review and Perspective
Endocr Metab Immune Disord Drug Targets 26, E18715303401342 (2026); https://doi.org/10.2174/0118715303401342250514102731
/content/journals/emiddt/10.2174/0118715303401342250514102731
/content/journals/emiddt/10.2174/0118715303401342250514102731
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  • Article Type:     Review Article
Keyword(s): damage-associated molecular patterns; Ischemia-reperfusion injury; next-generation therapies; pharmacological strategies; systemic homeostasis; therapeutic advances

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