2. Academic Validation
  3. Hypothermic machine perfusion attenuates DCD liver ischemia reperfusion injury via the YAP1/P53-mediated micromitophagy pathway

Hypothermic machine perfusion attenuates DCD liver ischemia reperfusion injury via the YAP1/P53-mediated micromitophagy pathway

  • Free Radic Biol Med. 2026 Jul:250:174-188. doi: 10.1016/j.freeradbiomed.2026.03.060.
Jia Liu 1,  Zhongzhong Liu 2,  Qifa Ye 2,  Qin Deng 1,  Zhihui Fu 1,  Fuping Cao 1,  Jun Luo 2,  Zhongshan Lu 2,  Jiansheng Xiao 3,  Qi Xiao 4
Affiliations

Affiliations

  • 1 Department of Transplantation, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 17 Yongwai Zhengjie Street, Nanchang, 330006, Jiangxi, China.
  • 2 National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Clinical Research Center for Natural Polymer Biological Liver, Hubei Engineering Center of Natural Polymer-Based Medical Materials, Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Wuhan, 430071, Hubei, China.
  • 3 Department of Transplantation, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 17 Yongwai Zhengjie Street, Nanchang, 330006, Jiangxi, China. Electronic address: [email protected].
  • 4 Department of Transplantation, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 17 Yongwai Zhengjie Street, Nanchang, 330006, Jiangxi, China. Electronic address: [email protected].
PMID: 41895416 DOI: 10.1016/j.freeradbiomed.2026.03.060
Abstract

Donation after circulatory death (DCD) livers are subjected to severe ischemia-reperfusion injury (IRI) during transplantation. Hypothermic machine perfusion (HMP) offers superior mitochondria protection compared with conventional cold storage (CS), yet the underlying molecular mechanisms remain incompletely understood. In this study, we investigated the mechanistic basis of HMP protection using a rat DCD liver model combined with an in vitro hypoxia/reoxygenation model in human umbilical vein endothelial cells (HUVECs). Rats were subjected to 30 min of warm ischemia followed by CS, HMP and normothermic machine perfusion (NMP). HMP significantly ameliorated liver dysfunction, histopathological damage, oxidative stress and inflammation compared with CS. Mechanistically, HMP upregulated yes-associated protein 1 (YAP1) expression and promoted P53 nuclear translocation, thereby enhancing the expression of microautophagy-related proteins including mitochondria-eating protein (MIEAP), BCL2 interacting protein 3 (BNIP3) and BNIP3-like (BNIP3L), and facilitating the formation of mitochondrial-derived vesicles (MDVs). These effects were abrogated by the YAP1 inhibitor verteporfin in vivo and by YAP1 knockdown or MIEAP silencing in vitro. Collectively, our findings demonstrate that HMP reduced oxidative damage and inflammation of DCD liver through YAP1/P53-mediated micromitophagy.

Keywords

Donation after circulatory death liver; Hypothermic machine perfusion; Ischemia reperfusion injury; Micromitophagy; P53; YAP1.

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