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

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.