ALKBH5 Protects Against Hepatic Ischemia-Reperfusion Injury by Regulating YTHDF1-Mediated YAP Expression.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Reperfusion Injury*/metabolism ; Reperfusion Injury*/genetics ; Reperfusion Injury*/pathology ; AlkB Homolog 5, RNA Demethylase*/metabolism ; AlkB Homolog 5, RNA Demethylase*/genetics ; RNA-Binding Proteins*/metabolism ; RNA-Binding Proteins*/genetics ; YAP-Signaling Proteins*/metabolism ; Hepatocytes*/metabolism ; Liver*/metabolism ; Liver*/pathology; Animals ; Mice ; Male ; Adaptor Proteins, Signal Transducing/metabolism ; Adaptor Proteins, Signal Transducing/genetics ; Cell Proliferation ; Humans ; Mice, Inbred C57BL ; Adenosine/analogs & derivatives ; Adenosine/metabolism ; Gene Expression Regulation ; RNA Stability

Ischemia/reperfusion (I/R) injury with severe cell death is a major complication involved in liver transplantation and resection. The identification of key regulators improving hepatocyte activity may provide potential strategies to clinically resolve I/R-induced injury. N ⁶ -methyladenosine (m ⁶ A) RNA modification is essential for tissue homeostasis and pathogenesis. However, the potential involvement of m ⁶ A in the regulation of hepatocyte activity and liver injury has not been fully explored. In the present study, we found that hepatocyte AlkB homolog H5 (ALKBH5) levels were decreased both in vivo and in vitro I/R models. Hepatocyte-specific ALKBH5 overexpression effectively attenuated I/R-induced liver necrosis and improved cell proliferation in mice. Mechanistically, ALKBH5-mediated m ⁶ A demethylation improved the mRNA stability of YTH N ⁶ -methyladenosine RNA-binding protein 1 (YTHDF1), thereby increasing its expression, which consequently promoted the translation of Yes-associated protein (YAP). In conclusion, ALKBH5 is a regulator of hepatic I/R injury that improves hepatocyte repair and proliferation by maintaining YTHDF1 stability and YAP content. The ALKBH5-m ⁶ A-YTHDF1-YAP axis represents promising therapeutic targets for hepatic I/R injury to improve the prognosis of liver surgery.

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82100672 National Natural Science Foundation of China; 2021CFB207 Natural Science Foundation of Hubei Province of China; for P.X. W. Wuhan Yellow Crane Talents Program; WX21Q01 Wuhan Municipal Health Commission

Keywords: ALKBH5; apoptosis; hepatocyte proliferation; ischemia–reperfusion injury

EC 1.14.11.- (AlkB Homolog 5, RNA Demethylase)
0 (RNA-Binding Proteins)
0 (YAP-Signaling Proteins)
0 (Adaptor Proteins, Signal Transducing)
EC 1.14.11.- (ALKBH5 protein, mouse)
0 (Ythdf1 protein, mouse)
0 (Yap1 protein, mouse)
CLE6G00625 (N-methyladenosine)
K72T3FS567 (Adenosine)
EC 1.14.11.- (ALKBH5 protein, human)

Date Created: 20241109 Date Completed: 20241109 Latest Revision: 20241116

20241116

PMC11546256

10.3390/ijms252111537

39519091