{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Hepatobiliary Center and Transplantation Center, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China.",
    "Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310000, China.",
    "Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China.",
    "Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital, Hangzhou 310022, China.",
    "Key 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.",
    "Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou 310006, China.",
    "General 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."
  ],
  "article_type": "research support, non u.s. gov't",
  "arxiv": null,
  "author_total": 15,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Fengqiang Gao"
    },
    {
      "affs": [
        1
      ],
      "name": "Ye Tao"
    },
    {
      "affs": [
        1
      ],
      "name": "Zijian Lou"
    },
    {
      "affs": [
        2
      ],
      "name": "Jinjian Li"
    },
    {
      "affs": [
        1
      ],
      "name": "Libin Dong"
    },
    {
      "affs": [
        1
      ],
      "name": "Yuhang Huang"
    },
    {
      "affs": [
        1
      ],
      "name": "Xiao Tang"
    },
    {
      "affs": [
        1
      ],
      "name": "Hanzhi Xu"
    },
    {
      "affs": [
        1
      ],
      "name": "Zhoucheng Wang"
    },
    {
      "affs": [
        3
      ],
      "name": "Shusen Zheng"
    },
    {
      "affs": [
        4
      ],
      "name": "Lixing Zhan"
    },
    {
      "affs": [
        2
      ],
      "name": "Xinyu Yang"
    },
    {
      "affs": [
        5
      ],
      "name": "Shengjun Xu"
    },
    {
      "affs": [
        6
      ],
      "name": "Kai Wang"
    },
    {
      "affs": [
        0
      ],
      "name": "Xiao Xu"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/23yzx905j646n.bib",
  "cited_by": 0,
  "doi": "10.7150/ijbs.132770",
  "fulltext_url": "https://europepmc.org/articles/PMC13685614",
  "id": "23yzx905j646n",
  "issns": [
    "1449-2288"
  ],
  "landing_url": "https://europepmc.org/article/MED/42909919",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2746|Organ Transplantation Techniques and Outcomes"
    ]
  ],
  "openalex": "W7214603469",
  "pdf_url": "https://europepmc.org/articles/PMC13685614?pdf=render",
  "pmcid": "PMC13685614",
  "pmid": "42909919",
  "published": "2026-09-11",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/23yzx905j646n.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:14Z",
      "native_id": "MED:42909919",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42909919"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2746|Organ Transplantation Techniques and Outcomes",
      "subfield": "surgery"
    }
  ],
  "title": "PAK1 Promotes Gluconeogenesis Via the ACSS2/KAT2A/PCK1 Complex to Attenuate Steatotic Liver Ischemia-Reperfusion Injury.",
  "title_text": "PAK1 Promotes Gluconeogenesis Via the ACSS2/KAT2A/PCK1 Complex to Attenuate Steatotic Liver Ischemia-Reperfusion Injury.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:20:14Z",
  "url": "https://research.draconitic.com/paper/23yzx905j646n",
  "venue": "International journal of biological sciences",
  "versions": []
}