{
  "abstract": "Background Acute-on-chronic liver failure (ACLF) is characterised by intense systemic inflammation and high short-term mortality, yet effective targeted therapies are lacking.Objective To explore monocyte heterogeneity in HBV-related ACLF (HBV-ACLF) to identify specific subsets and associated therapeutic targets.Design Peripheral blood mononuclear cells from healthy controls (n=4), patients with acute decompensation (n=5), and patients with ACLF (n=9) underwent single-cell RNA sequencing (scRNA-seq). Findings were integrated with hepatic scRNA-seq, bulk transcriptomics, multiplex immunohistochemistry and in vitro functional assays. The in vivo roles of candidate targets were validated in two murine ACLF models.Results We identified a distinct RETN + monocyte subset that was expanded in the circulation and liver of patients with HBV-ACLF. These RETN+ monocytes displayed a transcriptional programme enriched for anti-inflammatory and pro-resolving signatures, including MS1-B-like features. Interleukin-6 promoted the expansion of RETN+ monocyte via the JAK/STAT3/RUNX1 signalling axis. In murine ACLF models, neutralisation of Resistin exacerbated liver injury, increased systemic cytokine levels and augmented hepatocyte apoptosis. Conversely, administration of recombinant Resistin mitigated liver damage, diminished levels of inflammatory cytokines and improved survival. Mechanistically, Resistin activated PI3K/AKT signalling in hepatocytes, preserved the Bcl-2/Bax balance and suppressed intrinsic apoptosis. Clinically, plasma Resistin levels in HBV-ACLF patients inversely correlated with systemic inflammatory markers, liver injury, ACLF severity scores (Model for End-Stage Liver Disease, Chronic Liver Failure Consortium ACLF score) and short-term mortality.Conclusions RETN + monocytes constitute a distinct immunoregulatory subset enriched in HBV-ACLF, and their product, Resistin, exerts significant hepatoprotective and anti-inflammatory effects. These findings highlight RETN+ monocytes and Resistin as promising immunotherapeutic targets for HBV-ACLF.",
  "authors": [
    {
      "affiliations": [
        "State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China"
      ],
      "name": "Xianbin Xu"
    },
    {
      "affiliations": [
        "State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China"
      ],
      "name": "Jiyang Chen"
    },
    {
      "affiliations": [
        "State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China"
      ],
      "name": "Xia Yu"
    },
    {
      "affiliations": [
        "Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China",
        "Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang, China"
      ],
      "name": "Zhiwei Li"
    },
    {
      "affiliations": [
        "State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China"
      ],
      "name": "Jianing Chen"
    },
    {
      "affiliations": [
        "State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China"
      ],
      "name": "Danfeng Fang"
    },
    {
      "affiliations": [
        "Emergency and Trauma Centre, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China"
      ],
      "name": "Xingchen Lin"
    },
    {
      "affiliations": [
        "State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China"
      ],
      "name": "Huilan Tu"
    },
    {
      "affiliations": [
        "State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China"
      ],
      "name": "Xinyi Xu"
    },
    {
      "affiliations": [
        "State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China"
      ],
      "name": "Sisi Yang"
    },
    {
      "affiliations": [
        "State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China"
      ],
      "name": "Jinlin Cheng"
    },
    {
      "affiliations": [
        "Department of Infectious Diseases, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, China"
      ],
      "name": "Kai Gong"
    },
    {
      "affiliations": [
        "State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China"
      ],
      "name": "Haoda Weng"
    },
    {
      "affiliations": [
        "State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China"
      ],
      "name": "Yue Yu"
    },
    {
      "affiliations": [
        "State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China"
      ],
      "name": "Xiuding Zhang"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Lishui People’s Hospital, Lishui, Zhejiang, China"
      ],
      "name": "Yan Lan"
    },
    {
      "affiliations": [
        "Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China",
        "Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang, China"
      ],
      "name": "Biao Li"
    },
    {
      "affiliations": [
        "Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China",
        "Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang, China"
      ],
      "name": "Guoqiang Cao"
    },
    {
      "affiliations": [
        "Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China",
        "Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang, China"
      ],
      "name": "Hai Chen"
    },
    {
      "affiliations": [
        "Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China",
        "Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang, China"
      ],
      "name": "Leiming Chen"
    },
    {
      "affiliations": [
        "State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China"
      ],
      "name": "Xiaohan Qian"
    },
    {
      "affiliations": [
        "Department of Clinical Laboratory, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, China"
      ],
      "name": "Wenzheng Han"
    },
    {
      "affiliations": [
        "Emergency and Trauma Centre, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China"
      ],
      "name": "Meng Jiang"
    },
    {
      "affiliations": [
        "State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China"
      ],
      "name": "Weibo Du"
    },
    {
      "affiliations": [
        "State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China"
      ],
      "name": "Yida Yang"
    },
    {
      "affiliations": [
        "State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China"
      ],
      "name": "Jifang Sheng"
    },
    {
      "affiliations": [
        "State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China",
        "Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong, China"
      ],
      "name": "Xiaopeng Wu"
    },
    {
      "affiliations": [
        "State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China"
      ],
      "name": "Yu Shi"
    }
  ],
  "title": "Single-cell analysis identifies RETN+ monocyte-derived Resistin as a therapeutic target in hepatitis B virus-related acute-on-chronic liver failure",
  "uid": "942fc59e-0a87-544e-8be2-a0af1ea4a0df"
}