Skip to content
DraconiticResearch
Search Sources API
203,234 studies31 sourcesUpdated 15 min ago
Peer-reviewedCC BYInternational journal of biological sciences

PAK1 Promotes Gluconeogenesis Via the ACSS2/KAT2A/PCK1 Complex to Attenuate Steatotic Liver Ischemia-Reperfusion Injury.

  • Fengqiang Gao1
  • Ye Tao2
  • Zijian Lou2
  • Jinjian Li3
  • Libin Dong2
  • Yuhang Huang2
  • Xiao Tang2
  • Hanzhi Xu2
  • Zhoucheng Wang2
  • Shusen Zheng4
  • Lixing Zhan5
  • Xinyu Yang3
3 more authors
  • Shengjun Xu6
  • Kai Wang7
  • Xiao Xu1
7 affiliations
  1. 1Hepatobiliary Center and Transplantation Center, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China.
  2. 2Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310000, China.
  3. 3Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China.
  4. 4Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital, Hangzhou 310022, China.
  5. 5Key Laboratory of Nutrition, Metabolism, and Food Safety, Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of the Chinese Academy of Sciences, Shanghai 200031, China.
  6. 6Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou 310006, China.
  7. 7General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou 310024, China.
Read full textPDFDOICite

Abstract

Ischemia-reperfusion (IR) injury is particularly severe in steatotic livers, substantially increasing the risk of graft failure. The growing use of steatotic grafts amid donor shortages has therefore heightened the clinical importance of this problem. The conserved serine/threonine kinase p21-activated kinase 1 (PAK1) regulates cell migration, growth, and redox homeostasis, but its role in steatotic liver IR injury remains unclear. To address this question, we examined the association between PAK1 expression in human steatotic liver grafts and clinical outcomes in 74 liver transplantation (LT) recipients. Liver function, inflammation, and apoptosis were assessed using liver enzyme assays, F4/80 and Ly-6G immunostaining, and TUNEL staining, respectively. Co-immunoprecipitation and RNA sequencing were performed to elucidate the underlying molecular mechanisms. High PAK1 levels in steatotic liver grafts were associated with improved graft function and recipient survival after LT. Consistent with these clinical findings, PAK1 knockout exacerbated IR-induced hepatic inflammation and hepatocyte apoptosis, whereas PAK1 overexpression conferred protection; these findings were corroborated in vitro. Mechanistically, PAK1 interacted directly with ACSS2 and mediated ACSS2 phosphorylation at S267. Phosphorylated ACSS2 subsequently recruited KAT2A to form a multiprotein complex that locally catalyzed PCK1 K547 lactylation, thereby promoting gluconeogenesis. This process suppressed reactive oxygen species (ROS) production and enhanced energy supply. Moreover, fingolimod effectively protected steatotic livers against IR injury in the experimental model. Together, these findings highlight PAK1 as an important regulator of gluconeogenesis through the ACSS2-KAT2A-PCK1 complex and provide new insights into therapeutic strategies for protecting steatotic liver grafts against IR injury.

Related

  1. Dynamics of cell states and alternative splicing following kidney ischemia-reperfusion injury
    Dana Markiewitz, Jacob Goldberger, Tomer Kalisky
    Scientific ReportsPeer-reviewedCC BY-NC-ND 4.0Full textGeneral medicineCrossref
  2. ACSS2 phosphorylation at Ser659 attenuates neuronal apoptosis induced by cerebral ischemia-reperfusion by initiating autophagy
    Aman Hadierbieke, Amina Buerlike, Haicheng Xia
    Scientific ReportsPeer-reviewedCC BY-NC-ND 4.0Full textEpidemiology & public healthCrossref
  3. Myocardial Ischemia-Reperfusion Injury: Molecular Mechanisms and Innovative Therapeutic Strategies
    Dong Zhang, Xiaoting Yang, Shengyu Gong +4
    Reviews in cardiovascular medicinePeer-reviewedCC BYFull textCardiovascular medicineEurope PMC
  4. AN INTEGRATED HEART-ON-A-CHIP NAM RESOLVES DISTINCT CLINICAL PHENOTYPES OF MYOCARDIAL ISCHEMIA-REPERFUSION INJURY
    Khanh Tran, Ashley Roselynn Vincent, Caroline Whitmer +2
    bioRxivPreprintAll rights reservedFull textPhysiologybioRxivPMC
  5. Perioperative sophocarpine protects against testicular ischemia/reperfusion injury by blocking JNK/p38 signaling
    Pengyu Jia, Ziyue Ma, Lei Du +5
    Scientific ReportsPeer-reviewedCC BY-NC-ND 4.0Full textObstetrics, gynaecology & paediatricsCrossref

Cite

BibTeXRIS
BibTeX
@article{gao2026pak1,
  title = {{PAK1 Promotes Gluconeogenesis Via the ACSS2/KAT2A/PCK1 Complex to Attenuate Steatotic Liver Ischemia-Reperfusion Injury.}},
  author = {Fengqiang Gao and Ye Tao and Zijian Lou and Jinjian Li and Libin Dong and Yuhang Huang and Xiao Tang and Hanzhi Xu and Zhoucheng Wang and Shusen Zheng and Lixing Zhan and Xinyu Yang and Shengjun Xu and Kai Wang and Xiao Xu},
  journal = {International journal of biological sciences},
  year = {2026},
  month = sep,
  doi = {10.7150/ijbs.132770},
  url = {https://europepmc.org/article/MED/42909919},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - PAK1 Promotes Gluconeogenesis Via the ACSS2/KAT2A/PCK1 Complex to Attenuate Steatotic Liver Ischemia-Reperfusion Injury.
AU  - Fengqiang Gao
AU  - Ye Tao
AU  - Zijian Lou
AU  - Jinjian Li
AU  - Libin Dong
AU  - Yuhang Huang
AU  - Xiao Tang
AU  - Hanzhi Xu
AU  - Zhoucheng Wang
AU  - Shusen Zheng
AU  - Lixing Zhan
AU  - Xinyu Yang
AU  - Shengjun Xu
AU  - Kai Wang
AU  - Xiao Xu
PY  - 2026
DA  - 2026/09/11
JO  - International journal of biological sciences
DO  - 10.7150/ijbs.132770
UR  - https://europepmc.org/article/MED/42909919
AB  - Ischemia-reperfusion (IR) injury is particularly severe in steatotic livers, substantially increasing the risk of graft failure. The growing use of steatotic grafts amid donor shortages has therefore heightened the clinical importance of this problem. The conserved serine/threonine kinase p21-activated kinase 1 (PAK1) regulates cell migration, growth, and redox homeostasis, but its role in steatotic liver IR injury remains unclear. To address this question, we examined the association between PAK1 expression in human steatotic liver grafts and clinical outcomes in 74 liver transplantation (LT) recipients. Liver function, inflammation, and apoptosis were assessed using liver enzyme assays, F4/80 and Ly-6G immunostaining, and TUNEL staining, respectively. Co-immunoprecipitation and RNA sequencing were performed to elucidate the underlying molecular mechanisms. High PAK1 levels in steatotic liver grafts were associated with improved graft function and recipient survival after LT. Consistent with these clinical findings, PAK1 knockout exacerbated IR-induced hepatic inflammation and hepatocyte apoptosis, whereas PAK1 overexpression conferred protection; these findings were corroborated in vitro. Mechanistically, PAK1 interacted directly with ACSS2 and mediated ACSS2 phosphorylation at S267. Phosphorylated ACSS2 subsequently recruited KAT2A to form a multiprotein complex that locally catalyzed PCK1 K547 lactylation, thereby promoting gluconeogenesis. This process suppressed reactive oxygen species (ROS) production and enhanced energy supply. Moreover, fingolimod effectively protected steatotic livers against IR injury in the experimental model. Together, these findings highlight PAK1 as an important regulator of gluconeogenesis through the ACSS2-KAT2A-PCK1 complex and provide new insights into therapeutic strategies for protecting steatotic liver grafts against IR injury.
SN  - 1449-2288
ER  -