SAA/FPR2 Signaling Between Pericentral Hepatocytes and Macrophages Exacerbates Zonated Liver Transplant Injury

  • Adv Sci (Weinh). 2026 Jun;13(34):e22891. doi: 10.1002/advs.202522891.
Feng Zhang  1  2  3 ,  Rong Li  2 ,  Tingting Wang  1  2 ,  Jianhao Zhang  1  2 ,  Zhengqi Wu  1  2 ,  Qiang You  1  2 ,  Xuying Liu  1  2 ,  Cuicui Xiao  4 ,  Jiebin Zhang  1  2 ,  Haitian Chen  1  2 ,  Jiaqi Xiao  1  2 ,  Jia Yao  1  2 ,  Jun Zheng  1  2 ,  Yingcai Zhang  1  2  5 ,  Hua Li  1  2 ,  Shuhong Yi  1  2 ,  Yang Yang  1  2 ,  Qi Zhang  3 ,  Xiaofeng Yuan  6 ,  Yasong Liu  1  2
Affiliations
  • 1. Department of Hepatic Surgery and Liver Transplantation Center, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
  • 2. Guangdong Provincial Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 3. Cell-gene Therapy Translational Medicine Research Center, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
  • 4. Department of Anesthesiology, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
  • 5. Department of Hepatobiliary Surgery, People's Hospital of Xinjiang Uyghur Autonomous Region, Urumqi, Xinjiang, China.
  • 6. Department of General Intensive Care Unit, Lingnan Hospital, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
PMID: 41904943 DOI: 10.1002/advs.202522891
Abstract

Liver transplantation (LT) grafts exhibit selective pericentral hepatic ischemia-reperfusion injury (HIRI), but the zonal mechanism is unclear. To address this, we integrated single-cell and spatial transcriptomics with chromatin accessibility profiling, proteomics, and bulk RNA-seq, then validated key findings in clinical LT specimens, mouse HIRI models, and in vitro assays. Across datasets, HIRI disproportionately aggravated pericentral hepatocyte injury and markedly coincided with heightened macrophage crosstalk. Mechanistically, we identified FOXO1-dominated SAA secretion from pericentral hepatocytes that promotes FPR2+ macrophages recruitment and activation, thereby exacerbating pericentral-predominant hepatocyte injury. Supporting this mechanism, pharmacological inhibition of SAA-driven proinflammatory activity using the SAA inhibitor Amilo-5MER reduced macrophage accumulation, alleviated pericentral hepatocyte damage, and mitigated zonal disparities. Collectively, these findings delineate the emerging role of FOXO1/SAA/FPR2 axis in pericentral vulnerability, pinpointing SAA as a tractable therapeutic target to ameliorate zonal injury and improve graft outcomes after LT.

Keywords
Amilo‐5MER; SAA/FPR2 signaling; hepatic ischemia‐reperfusion injury; liver transplantation; liver zonation.
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