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Review
. 2023 Apr 5;9(1):115.
doi: 10.1038/s41420-023-01387-0.

Autophagy in hepatic ischemia-reperfusion injury

Benliang Mao #  1   2 , Wei Yuan #  1 , Fan Wu  1 , Yong Yan  1 , Bailin Wang  3   4
Affiliations
Review

Autophagy in hepatic ischemia-reperfusion injury

Benliang Mao et al. Cell Death Discov. .

Erratum in

Abstract

Hepatic ischemia-reperfusion injury (HIRI) is a major complication of liver resection or liver transplantation that can seriously affect patient's prognosis. There is currently no definitive and effective treatment strategy for HIRI. Autophagy is an intracellular self-digestion pathway initiated to remove damaged organelles and proteins, which maintains cell survival, differentiation, and homeostasis. Recent studies have shown that autophagy is involved in the regulation of HIRI. Numerous drugs and treatments can change the outcome of HIRI by controlling the pathways of autophagy. This review mainly discusses the occurrence and development of autophagy, the selection of experimental models for HIRI, and the specific regulatory pathways of autophagy in HIRI. Autophagy has considerable potential in the treatment of HIRI.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Steps and machinery of autophagy.
Stress signals such as hunger, hypoxia, shock, oxidative stress, and inflammatory responses activate AMPK and inhibit mTOR. As their common target, the ULK1 complex triggers the nucleation of phagophore by phosphorylating the Beclin-1 complex and activating ATG9, recruiting membrane sources to form the initial membrane skeleton—omegasome. The ATG12-ATG5-ATG16 complex enhances the conjugation of LC3-II to PE, thereby assembling on the forming phagophore to which autophagic targets are recruited. Targets, which can be labeled by ubiquitin chains, as well as cargo receptors, recruit membrane components to elongate the membrane structure and cargo (damaged organelle, protein aggregate) so as to promote maturation. Cargo needs to be decorated with delicious labels (most prominently ubiquitin (Ub) chains) so that autophagic receptors (p62) recognize it and that it can be swallowed by autophagosome. After lysosomal fusion, the contents of the autolysosome are degraded, and nutrients are recycled by the cell. Abbreviations: ULK1 Unc-51-like kinase 1; ATG autophagy-related protein; FIP200 RB1-inducible coiled-coil protein 1; VPS vacuolar protein sorting; AMBRA1 autophagy and Beclin-1 regulator 1; p115 vesicular transport factor; LC3 microtubule-associated protein light chain 3; PE phosphatidylethanolamine; p62 SQSTM1 gene and sequestosome-1; Ub ubiquitin.
Fig. 2
Fig. 2. Effects of autophagy on HIRI via the AMPK/mTOR pathway.
Abbreviations: IL37 interleukin 37; 3-MA 3-methyladenine; HBSP Helix B surface peptide; Ly294002 Akt inhibitor.
Fig. 3
Fig. 3. Pathway network for autophagy to affect HIRI.
MTOR is the hub of autophagy regulation. The AMPK pathway and Sirt-FoxO3α pathway inhibit mTOR and thus activate autophagy, while the PI3K-AKT pathway activates mTOR and thus hinders autophagy. Beclin-1 is another key protein in the regulation of autophagy. ERK inhibits Bcl-2 and Beclin-1 binding and exerts autophagy activation, while P38 and JNK appear to exhibit opposite effects. The Nrf2/HO-1 pathway and the PINK1/Parkin pathway are also two important pathways that activate autophagy. Finally, activated autophagy can attenuate HIRI either directly or by inhibiting ER stress and suppressing NLRP3 inflammasome. AMPK adenosine 5′-monophosphate-activated protein kinase, mTOR mammalian target of rapamycin, PI3K phosphoinositide 3-kinase, AKT protein kinase B, PIP3 phosphatidyl inositol-3,4,5-triphosphate, Sirt1 Sirtuin 1, FoxO3α transcription factor, ERK extracellular signal-regulated kinase, JNK c-Jun N-terminal kinase, Nrf2 Nuclear factor erythroid 2- related factor 2, Keap1 Kelch-like erythroid-associated protein 1, Pink1, phosphatase and tensin homolog-induced putative kinase 1, Parkin an E3 ubiquitin ligase encoded by the gene Park2, NLRP3, nucleotide-binding domain leucine-rich repeat containing family pyrin domain containing 3.
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References

    1. Chan TS, Cassim S, Raymond VA, Gottschalk S, Merlen G, Zwingmann C, et al. Upregulation of Krebs cycle and anaerobic glycolysis activity early after onset of liver ischemia. PloS One. 2018;13:e0199177. doi: 10.1371/journal.pone.0199177. - DOI - PMC - PubMed
    1. Wang JH, Behrns KE, Leeuwenburgh C, Kim JS. Critical role of autophage in ischemia/reperfusion injury to aged livers. Autophagy. 2012;8:140–1. doi: 10.4161/auto.8.1.18391. - DOI - PMC - PubMed
    1. Liu J, Zhang W, Zhou C, Li M, Wang X, Zhang W, et al. Precision navigation of hepatic ischemia–reperfusion injury guided by lysosomal viscosity-activatable NIR-II fluorescence. J Am Chem Soc. 2022;144:13586–99. doi: 10.1021/jacs.2c03832. - DOI - PMC - PubMed
    1. Cao Q, Luo J, Xiong Y, Liu Z, Ye Q. 25-Hydroxycholesterol mitigates hepatic ischemia reperfusion injury via mediating mitophagy. Int Immunopharmacol. 2021;96:107643. doi: 10.1016/j.intimp.2021.107643. - DOI - PubMed
    1. Chen K, Li JJ, Li SN, Feng J, Liu T, Wang F, et al. 15-Deoxy-Δ12,14-prostaglandin J2 alleviates hepatic ischemia-reperfusion injury in mice via inducing antioxidant response and inhibiting apoptosis and autophagy. Acta Pharmacol Sin. 2017;38:672–87. doi: 10.1038/aps.2016.108. - DOI - PMC - PubMed