Dissecting the liver inflammation ecosystem identifies annexin A1 as a pro-resolving target for liver failure
Abstract
Background and Aims: Acute-on-chronic liver failure (ACLF) is driven by systemic inflammation and immune dysregulation. This study aims to characterize the immune landscape in ACLF and identify potential therapeutic targets. Approach and Results: We employed single-cell RNA sequencing, vision spatial sequencing, bulk RNA sequencing, and bioinformatics analysis to profile immune cells in ACLF livers compared to acute liver failure, decompensated cirrhosis, and controls. ACLF livers exhibited a distinct immune signature with increased neutrophils, particularly CCL4 + subsets, which drive unresolved inflammation by recruiting additional neutrophils and inflammatory CD14 + S100A9 + monocytes. Resident KCs were reduced, and monocytes differentiated into TREM2 + macrophages with an M1-like pro-inflammatory phenotype, exacerbating inflammation. Additionally, lymphoid cells showed significant dysfunction, with reduced NK cells and relatively expanded T cells exhibiting diminished cytotoxicity or pro-inflammatory cytokine production. Cell–cell communication analysis identified the ANXA1–FPR1 axis as a key interaction between T cells and myeloid cells, serving as a negative feedback mechanism to dampen inflammation. Plasma and hepatic ANXA1 levels were elevated in ACLF patients, correlating with disease severity. In the preclinical model, the ANXA1 peptide Ac2–26 improved liver function, reduced inflammation, and promoted macrophage polarization from M1 to M2. In vitro, Ac2–26 inhibited CCL4-mediated monocyte chemotaxis and M1 polarization, effects partially blocked by the FPR1 inhibitor Randialic acid B. Mechanically, Ac2–26 activated AMPK and inhibited mTOR signaling. Conclusions: Our findings provide a comprehensive immune profile in ACLF and highlight ANXA1 as a potential therapeutic target for resolving immune dysregulation and improving outcomes in ACLF.
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AMPK plays a central role in macrophage metabolic reprogramming.
“AMP-activated protein kinase (AMPK), a master regulator of cellular energy homeostasis, plays a central role in this process (33–36).”
From Strategies to promote liver fibrosis amelioration with involvement of restorative macrophages (2026) · cites this paper as [33]
Cites
AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1
Kim, J., Kundu, M., Viollet, B., & Guan, K.-L. (2011) · Nature Cell Biology · doi:10.1038/ncb2152 · Cited by 7,227 · see citing works
Resolving the fibrotic niche of human liver cirrhosis at single-cell level
Ramachandran, P., Dobie, R., Wilson-Kanamori, J. R., Dora, E. F., Henderson, B. E. P., Luu, N. T., Portman, J. R., Matchett, K. P., Brice, M., Marwick, J. A., et al. (2019) · Nature · doi:10.1038/s41586-019-1631-3 · Cited by 1,784 · see citing works
A pan-cancer single-cell transcriptional atlas of tumor infiltrating myeloid cells
Cheng, S., Li, Z., Gao, R., Xing, B., Gao, Y., Yang, Y., Qin, S., Zhang, L., Ouyang, H., Du, P., et al. (2021) · Cell · doi:10.1016/j.cell.2021.01.010 · Cited by 1,601 · see citing works
Self-citationSingle cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations
MacParland, S. A., Liu, J. C., Ma, X.-Z., Innes, B. T., Bartczak, A. M., Gage, B. K., Manuel, J., Khuu, N., Echeverri, J., Linares, I., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-06318-7 · Cited by 1,552 · see citing works
Macrophage heterogeneity in liver injury and fibrosis
Tacke, F., & Zimmermann, H. W. (2014) · Journal of Hepatology · doi:10.1016/j.jhep.2013.12.025 · Cited by 1,061 · see citing works
Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches
Guilliams, M., Bonnardel, J., Haest, B., Vanderborght, B., Wagner, C., Remmerie, A., Bujko, A., Martens, L., Thoné, T., Browaeys, R., et al. (2022) · Cell · doi:10.1016/j.cell.2021.12.018 · Cited by 985 · see citing works
Cross-tissue single-cell landscape of human monocytes and macrophages in health and disease
Mulder, K., Patel, A. A., Kong, W. T., Piot, C., Halitzki, E., Dunsmore, G., Khalilnezhad, S., Irac, S. E., Dubuisson, A., Chevrier, M., et al. (2021) · Immunity · doi:10.1016/j.immuni.2021.07.007 · Cited by 678 · see citing works
Self-citationAcute-on-Chronic Liver Failure
Arroyo, V., Moreau, R., & Jalan, R. (2020) · New England Journal of Medicine · doi:10.1056/nejmra1914900 · Cited by 657 · see citing works
Bonnardel, J., T’Jonck, W., Gaublomme, D., Browaeys, R., Scott, C. L., Martens, L., Vanneste, B., De Prijck, S., Nedospasov, S. A., Kremer, A., et al. (2019) · Immunity · doi:10.1016/j.immuni.2019.08.017 · Cited by 631 · see citing works
Neutrophil profiling illuminates anti-tumor antigen-presenting potency
Wu, Y. C., Ma, J., Yang, X., Fang, N., Zhang, T., Ji, S., Rao, D., Feng, H., Gao, K., Gu, X., et al. (2024) · Cell · doi:10.1016/j.cell.2024.02.005 · Cited by 441 · see citing works
Self-citationAdaptive immune cells temper initial innate responses
Dong Kim, K., Zhao, J., Auh, S., Yang, X., Du, P., Tang, H., & Fu, Y.-X. (2007) · Nature Medicine · doi:10.1038/nm1633 · Cited by 348 · see citing works
Global burden of disease: acute-on-chronic liver failure, a systematic review and meta-analysis
Gabriel Mezzano, P., Juanola, A., Cárdenas, A., Mezey, E., Hamilton, J. P., Pose, E., Graupera, I., Ginès, P., Solà, E., & Hernáez, R. (2021) · Gut · doi:10.1136/gutjnl-2020-322161 · Cited by 255 · see citing works
Xu, X., Gao, W., Li, L., Hao, J.-H., Yang, B., Wang, T., Li, L., Bai, X.-S., Li, F., Ren, H., et al. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02174-3 · Cited by 253 · see citing works
Self-citationBernsmeier, C., Triantafyllou, E., Brenig, R., Lebosse, F. J., Singanayagam, A., Patel, V. C., Pop, O. T., Khamri, W., Nathwani, R., Tidswell, R., et al. (2018) · Gut · doi:10.1136/gutjnl-2017-314184 · Cited by 159 · see citing works
Dib, L. H., Koneva, L. A., Edsfeldt, A., Zurke, Y.-X., Sun, J., Nitulescu, M., Attar, M., Lutgens, E., Schmidt, S., Lindholm, M., et al. (2023) · Nature Cardiovascular Research · doi:10.1038/s44161-023-00295-x · Cited by 150 · see citing works
Mahabeleshwar, G. H., Kawanami, D., Sharma, N., Takami, Y., Zhou, G., Shi, H., Nayak, L. V., Jeyaraj, D., Grealy, R., White, M., et al. (2011) · Immunity · doi:10.1016/j.immuni.2011.04.014 · Cited by 149 · see citing works
Lipid-associated macrophages' promotion of fibrosis resolution during MASH regression requires TREM2
Ganguly, S., Rosenthal, S. B., Ishizuka, K., Troutman, T. D., Rohm, T. V., Khader, N., Aleman-Muench, G., Sano, Y., Archilei, S., Soroosh, P., et al. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2405746121 · Cited by 145 · see citing works
Multimodal decoding of human liver regeneration
Matchett, K. P., Wilson-Kanamori, J. R., Portman, J. R., Kapourani, C. A., Fercoq, F., May, S., Zajdel, E., Beltran, M., Sutherland, E. F., Mackey, J. B. G., et al. (2024) · Nature · doi:10.1038/s41586-024-07376-2 · Cited by 140 · see citing works
Acute-on-chronic liver failure: Terminology, mechanisms and management
Vinay Kumar, B. R., & Sarin, S. K. (2023) · Clinical and Molecular Hepatology · doi:10.3350/cmh.2022.0103 · Cited by 129 · see citing works
Acute-on-chronic liver failure (ACLF): the ‘Kyoto Consensus’—steps from Asia
Choudhury, A. K., Kulkarni, A. V., Arora, V., Soin, A. S., Dökmeci, A. K., Chowdhury, A., Koshy, A., Duseja, A. K., Kumar, A., Mishra, A. K., et al. (2025) · Hepatology International · doi:10.1007/s12072-024-10773-4 · Cited by 93 · see citing works
Lymphocytes Support Oval Cell-Dependent Liver Regeneration
Strick‐Marchand, H., Masse‐Ranson, G., Weiss, M. C., & Santo, J. P. D. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.4.2764 · Cited by 85 · see citing works
Khanam, A., Trehanpati, N., Riese, P., Rastogi, A., Guzmán, C. A., & Sarin, S. K. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00464 · Cited by 78 · see citing works
TREM-2 plays a protective role in cholestasis by acting as a negative regulator of inflammation
Labiano, I., Agirre-Lizaso, A., Olaizola, P., Echebarria, A., Huici-Izagirre, M., Olaizola, I., Esparza-Baquer, A., Sharif, O., Hijona, E., Milkiewicz, P., et al. (2022) · Journal of Hepatology · doi:10.1016/j.jhep.2022.05.044 · Cited by 78 · see citing works
Deficiency of Annexin A1 in CD4+ T Cells Exacerbates T Cell–Dependent Inflammation
Yang, Y. H., Song, W., Deane, J. A., Kao, W., Ooi, J. D., Ngo, D., Kitching, A. R., Morand, E. F., & Hickey, M. J. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1202236 · Cited by 72 · see citing works
Self-citationAnnexin‐A1: The culprit or the solution?
Kelly, L., McGrath, S., Rodgers, L., McCall, K., Virlan, A. T., Dempsey, F. C., Crichton, S. J., & Goodyear, C. S. (2022) · Immunology · doi:10.1111/imm.13455 · Cited by 69 · see citing works
Levy, T., Voeltzke, K., Hruby, L. A., Alasad, K., Bas, Z., Snaebjornsson, M. T., Marciano, R., Scharov, K., Planque, M., Vriens, K., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-48386-y · Cited by 53 · see citing works
Khamri, W., Abeles, R. D., Hou, T. Z., Anderson, A. E., El-Masry, A., Triantafyllou, E., Bernsmeier, C., Larsen, F. S., Singanayagam, A., Kudo, N., et al. (2017) · Gastroenterology · doi:10.1053/j.gastro.2017.03.023 · Cited by 49 · see citing works
Mechanisms of immunity in acutely decompensated cirrhosis and acute‐on‐chronic liver failure
Engelmann, C., Zhang, I. W., & Clària, J. (2023) · Liver International · doi:10.1111/liv.15644 · Cited by 46 · see citing works
Feio‐Azevedo, R., Boesch, M., Radenkovic, S., Melkebeke, L. V., Smets, L., Wallays, M., Boeckx, B., Philips, G., de Oliveira, J. P., Ghorbani, M., et al. (2024) · Hepatology · doi:10.1097/hep.0000000000000907 · Cited by 25 · see citing works
Annexin A1 treatment prevents the evolution to fibrosis of experimental nonalcoholic steatohepatitis
Gadipudi, L. L., Ramavath, N. N., Provera, A., Reutelingsperger, C. P. M., Albano, E., Perretti, M., & Sutti, S. (2022) · Clinical Science · doi:10.1042/cs20211122 · Cited by 23 · see citing works
Kořínek, M., Hsieh, P.-S., Chen, Y., Hsieh, P., Chang, S.-H., Wu, Y., & Hwang, T. (2021) · Biochemical Pharmacology · doi:10.1016/j.bcp.2021.114596 · Cited by 23 · see citing works
Evidence-based incorporation of key parameters into MELD score for acute-on-chronic liver failure
Xia, Y., Zhou, R., Tan, W., Wang, X., Zheng, X., Huang, Y., Chen, J., Li, B., Liu, X., Li, Z., et al. (2024) · eGastroenterology · doi:10.1136/egastro-2024-100101 · Cited by 16 · see citing works
Self-citationOrtega‐Ribera, M., Zhuang, Y., Babuta, M., Brezáni, V., Joshi, R., Zsengellér, Z. K., Nagesh, P. T., Wang, Y., Bronson, R. T., & Szabó, G. (2024) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2024.101446 · Cited by 15 · see citing works
Zhang, J., Wang, H., Liu, J., Fu, L., & Peng, S. (2023) · Human Genomics · doi:10.1186/s40246-023-00534-z · Cited by 9 · see citing works
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Sorted by citations
Xu, X., Chen, J., Xia, Y., Li, Z., Chen, J., Fang, D., Lin, X., Tu, H., Xu, X., Yang, S., et al. (2025) · Gut · doi:10.1136/gutjnl-2025-335998 · Cited by 12 · see citing works
Self-citationStrategies to promote liver fibrosis amelioration with involvement of restorative macrophages
Aquino, J. B. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1792423 · Cited by 1 · see citing works
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Xiong, Q., Wang, J., Liu, Y., Wang, B., Wang, Q., & Cheng, A. (2025) · Medical Oncology · doi:10.1007/s12032-025-03137-x · Cited by 1 · see citing works
Wang, X., Wang, R., Zhang, H., & Shi, Y. (2026) · Infectious Microbes & Diseases · doi:10.1097/im9.0000000000000217 · Cited by 1 · see citing works
Self-citationSheng, L., Zhang, X., Weng, H., Deng, Q., Deng, M., Wu, X., 黄祖雄, Liu, S., Wu, R., Ma, C., et al. (2026) · PLoS ONE · doi:10.1371/journal.pone.0357491 · Cited by 1 · see citing works
Self-citationChen, J., Yang, S., Xu, X., Shi, Y., & Yang, Y. (2025) · Journal of Hepatology · doi:10.1016/j.jhep.2025.12.012
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Passenberg, M., Guntlisbergen, C., Nuruzade, N., Best, J., Hoyer, D. P., Neumann, U. P., Schmidt, H., Willuweit, K., Konstantis, G., & Rashidi‐Alavijeh, J. (2026) · Journal of Clinical Medicine · doi:10.3390/jcm15072635
Yu, Y., Li, M., Xie, Y., Wang, F.-S., & Shi, M. (2026) · Infectious Diseases & Immunity · doi:10.1097/id9.0000000000000212
Self-citationYin, J., Ding, L., Zhao, Z., Chen, X., Huang, J., Xiao, Y., Gu, L., Zhang, X., Tong, Q., & Zhang, Y. (2026) · Molecular Biomedicine · doi:10.1186/s43556-026-00448-x
Self-citationQiu, L., Dong, C., Zhao, R. Z., Ye, H., Gao, J., Chen, Y., Sun, C. X., & Gu, Z. (2026) · Aging Cell · doi:10.1111/acel.70486
Zou, G., Pu, L., Xiao, Z., Luo, W., Yu, T., Zhang, Y., & Zhang, L. (2026) · Journal of Translational Medicine · doi:10.1186/s12967-026-08376-8
Jia, J., Dong, Y.-H., Zhao, Y., Li, S.-Y., & Mou, T.-W. (2026) · Journal of Immunological Research · doi:10.1155/jimr/5421823
Tang, D., Wu, Y.-N., Ding, L., Ding, X.-L., Chen, J., Sun, Y.-T., Guo, J.-J., Lu, L.-J., & Wang, R.-Y. (2026) · Journal of Pharmacological Sciences · doi:10.1016/j.jphs.2026.08.006
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- Authors
- Yu, X., Tian, W., Bao, X., Li, Z., Tu, H., Xu, X., Chen, J., Zhang, Q., Chen, J., Liu, C., Dai, X., Xu, X., Weng, H., Yu, Y., Zhang, X., Zhou, R., Zhu, W., Lan, Y., Cheng, J., Xu, M., Wu, W., Huang, R., Yang, Y., Sheng, J., Guo, J., & Shi, Y.
- Affiliations
- First Affiliated Hospital Zhejiang University (CN)
- Jiangsu University (CN)
- Shanghai Jiao Tong University (CN)
- Nanjing Drum Tower Hospital (CN)
- Stanford Medicine (US)
- Corresponding author
- Yu, Xia
- Yu, Yue
- Sheng, Jifang
- Guo, Jing
- Shi, Yu
- ORCID
- Venue
- Hepatology
- Published
- 2025-06-12
- Volume
- 83
- Issue
- 5
- Pages
- 1174-1191
- ISSN
- 0270-9139 (ISSN-L)
- 1527-3350
- OpenAlex
- W4411629356
- Cited by
- 14
- References
- 34
- Citations by year
- 2026: 11 · 2025: 3
- FWCI
- 7.88
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hepatology › Liver Disease and Transplantation
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
- Keywords
- acute-on-chronic liver failure, liver inflammation, annexin A1, FPR1, neutrophils, carbon tetrachloride, monocyte chemotaxis, TREM2+ macrophages, macrophage polarization, NK cell dysfunction, T cell dysfunction, intercellular communication, AMPK/mTOR signaling, acute liver failure, decompensated cirrhosis
- MeSH terms
- Animals, Female, Humans, Liver, Macrophages, Male, Middle Aged, Neutrophils, Annexin A1, Receptors, Formyl Peptide, Mice, Acute-On-Chronic Liver Failure
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