SAA/FPR2 Signaling Between Pericentral Hepatocytes and Macrophages Exacerbates Zonated Liver Transplant Injury
Source abstract
Abstract
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.
Source: crossref · Quality: baseline
Research context
OpenAlex topics: Organ Transplantation Techniques and Outcomes · Liver physiology and pathology · FOXO transcription factor regulation
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
Affiliations
Department of Hepatic Surgery and Liver Transplantation Center the Third Affiliated Hospital of Sun Yat‐Sen University Guangzhou China
Guangdong Provincial Key Laboratory of Liver Disease Research the Third Affiliated Hospital of Sun Yat‐sen University Guangzhou China
Cell‐gene Therapy Translational Medicine Research Center the Third Affiliated Hospital of Sun Yat‐Sen University Guangzhou China
Department of Anesthesiology the Third Affiliated Hospital of Sun Yat‐Sen University Guangzhou China
Department of Hepatobiliary Surgery People's Hospital of Xinjiang Uyghur Autonomous Region Urumqi Xinjiang China
Department of General Intensive Care Unit Lingnan Hospital The Third Affiliated Hospital of Sun Yat‐Sen University Guangzhou China
Funding
National Key Research and Development Program of China · National Natural Science Foundation of China · Natural Science Foundation of Guangdong Province · China Postdoctoral Science Foundation
References (67)
Show source-provided references
1. 10.1016/S2468‐1253(23)00363‐110.1016/S2468‐1253(23)00363‐1 ↗
2. 10.1097/HEP.000000000000087310.1097/HEP.0000000000000873 ↗
3. 10.1016/j.livres.2022.08.00210.1016/j.livres.2022.08.002 ↗
4. 10.1016/S2468-1253(22)00268-010.1016/S2468-1253(22)00268-0 ↗
5. 10.3350/cmh.2024.022210.3350/cmh.2024.0222 ↗
6. 10.1016/j.jcmgh.2023.03.00310.1016/j.jcmgh.2023.03.003 ↗
7. 10.1038/s41419‐022‐04955‐x10.1038/s41419‐022‐04955‐x ↗
8. Bioinspired Spatially Ordered Multicellular Lobules for Liver Regeneration
9. 10.1016/j.scib.2024.02.03010.1016/j.scib.2024.02.030 ↗
10. 10.1038/s41575‐019‐0134‐x10.1038/s41575‐019‐0134‐x ↗
11. 10.1038/s41467-024-55325-410.1038/s41467-024-55325-4 ↗
12. 10.1146/annurev-pathmechdis-031521-02483110.1146/annurev-pathmechdis-031521-024831 ↗
13. 10.1038/s41588‐024‐01687‐w10.1038/s41588‐024‐01687‐w ↗
14. 10.1038/s41556‐023‐01316‐410.1038/s41556‐023‐01316‐4 ↗
15. 10.1016/j.stem.2022.04.00810.1016/j.stem.2022.04.008 ↗
16. 10.1002/hep.3056310.1002/hep.30563 ↗
17. 10.1038/s41467‐025‐59724‐z10.1038/s41467‐025‐59724‐z ↗
18. 10.1038/s41586‐025‐08850‐110.1038/s41586‐025‐08850‐1 ↗
19. 10.1016/j.jaut.2021.10271310.1016/j.jaut.2021.102713 ↗
20. 10.7150/ijbs.10944910.7150/ijbs.109449 ↗
21. 10.1038/s41575‐021‐00549‐810.1038/s41575‐021‐00549‐8 ↗
22. 10.1016/j.jhep.2025.08.00710.1016/j.jhep.2025.08.007 ↗
23. 10.1038/s41586-025-08677-w10.1038/s41586-025-08677-w ↗
24. 10.1097/HEP.000000000000142910.1097/HEP.0000000000001429 ↗
25. 10.1016/j.stem.2023.04.00710.1016/j.stem.2023.04.007 ↗
26. 10.1038/s41467‐024‐45439‐010.1038/s41467‐024‐45439‐0 ↗
27. 10.1016/j.cytogfr.2015.12.01010.1016/j.cytogfr.2015.12.010 ↗
28. 10.7150/ijbs.10082310.7150/ijbs.100823 ↗
29. 10.1038/s41467‐024‐46118‐w10.1038/s41467‐024‐46118‐w ↗
30. 10.1038/s41590‐020‐0698‐110.1038/s41590‐020‐0698‐1 ↗
31. 10.1038/s41467‐025‐59968‐910.1038/s41467‐025‐59968‐9 ↗
32. 10.1073/pnas.182028211610.1073/pnas.1820282116 ↗
33. 10.1038/s41419‐023‐05879‐w10.1038/s41419‐023‐05879‐w ↗
34. 10.1016/j.redox.2024.10325810.1016/j.redox.2024.103258 ↗
35. 10.1186/s12951‐025‐03729‐910.1186/s12951‐025‐03729‐9 ↗
36. 10.1038/s41419‐020‐03374‐010.1038/s41419‐020‐03374‐0 ↗
37. 10.1016/j.ccr.2025.21735710.1016/j.ccr.2025.217357 ↗
38. 10.1016/j.drup.2025.10134210.1016/j.drup.2025.101342 ↗
39. 10.1038/s41467-024-49202-310.1038/s41467-024-49202-3 ↗
40. 10.1097/HEP.000000000000059010.1097/HEP.0000000000000590 ↗
41. 10.1038/s42255-019-0109-910.1038/s42255-019-0109-9 ↗
42. 10.1002/advs.20240524010.1002/advs.202405240 ↗
43. 10.1016/j.drup.2024.10111510.1016/j.drup.2024.101115 ↗
44. 10.1093/bioinformatics/bty56010.1093/bioinformatics/bty560 ↗
45. 10.1093/nar/gkac95810.1093/nar/gkac958 ↗
46. 10.1038/s41587‐019‐0201‐410.1038/s41587‐019‐0201‐4 ↗
47. 10.1093/bioinformatics/btt65610.1093/bioinformatics/btt656 ↗
48. 10.1186/s13059‐014‐0550‐810.1186/s13059‐014‐0550‐8 ↗
49. 10.1038/nbt.151110.1038/nbt.1511 ↗
50. 10.1074/mcp.TIR119.00164610.1074/mcp.TIR119.001646 ↗
51. 10.1002/imt2.7002710.1002/imt2.70027 ↗
52. 10.1038/nmeth.192310.1038/nmeth.1923 ↗
53. Picard toolkit Broad Institute GitHub repository https://broadinstitute.github.io/picard/(2019).
54. 10.1038/s41598‐019‐45839‐z10.1038/s41598‐019‐45839‐z ↗
55. 10.1186/gb‐2008‐9‐9‐r13710.1186/gb‐2008‐9‐9‐r137 ↗
56. 10.1038/nature1073010.1038/nature10730 ↗
57. 10.1093/bioinformatics/btv14510.1093/bioinformatics/btv145 ↗
58. 10.1016/j.cell.2021.04.04810.1016/j.cell.2021.04.048 ↗
59. 10.1016/j.cels.2019.03.00310.1016/j.cels.2019.03.003 ↗
60. 10.1016/j.cels.2015.12.00410.1016/j.cels.2015.12.004 ↗
61. 10.1038/s41592‐023‐02014‐710.1038/s41592‐023‐02014‐7 ↗
62. 10.1073/pnas.050658010210.1073/pnas.0506580102 ↗
63. 10.1038/s41467‐019‐09234‐610.1038/s41467‐019‐09234‐6 ↗
64. 10.1093/bioadv/vbac01610.1093/bioadv/vbac016 ↗
65. 10.3390/biom1407074910.3390/biom14070749 ↗
66. 10.1093/nar/gkad105910.1093/nar/gkad1059 ↗
67. 10.1038/s41467‐021‐21246‐910.1038/s41467‐021‐21246‐9 ↗