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REVIEW ARTICLE

Spatial architecture of the pre-malignant niche in MASH: Multicellular signaling hubs orchestrating hepatocyte stress and carcinogenesis

Chengdong Zhu1,2 ,  Guanqi Liu2* ,  Chaochao Liu2,3*
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1 Department of Gastroenterology, The First People’s Hospital Of Wuhu, Wuhu, Anhui, China
2 Department of Gastroenterology, Nanjing Jiangbei Hospital, Nanjing, Jiangsu, China
3 Department of Gastroenterology, Ma’anshan Seventeenth Metallurgical Construction Hospital, Ma’anshan, Anhui, China
EJMO, 026060075 https://doi.org/10.36922/EJMO026060075
Received: 8 February 2026 | Revised: 15 April 2026 | Accepted: 17 April 2026 | Published online: 15 May 2026
© 2026 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution -Noncommercial 4.0 International License (CC-by the license) ( https://creativecommons.org/licenses/by-nc/4.0/ )
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Abstract

The transition from metabolic dysfunction-associated steatohepatitis to hepatocellular carcinoma is no longer considered genetic drift. Spatial transcriptomics has enabled the reconstruction of functional tissue atlases, moving beyond disconnected lists of cell types. This review explores the spatial heterogeneity of hepatocytes under chronic stress and proposes that “extreme stress responders” may serve as seeds of malignancy. Disease-specific multicellular neighborhoods involving scar-associated macrophages and reactive ductular cells, together with core signaling pathways such as lymphotoxin-beta–lymphotoxin-beta receptor and JAG1–NOTCH signaling, may drive hepatocellular stress and lineage transitions. Finally, we propose a “spatial blockade” framework for next-generation precision diagnostics and therapies.

Keywords
Spatial transcriptomics
Liver microenvironment
Hepatic lobule zonation
Multicellular niches
Cell communication
Hepatocellular carcinoma
Funding
This work was supported by the Technological Development Program of Ma’anshan (Grant No. YL-2023-29).
Conflict of interest
The authors declare no conflict of interest.
References
  1. Yasaka TM, Kim CK, Meadows V, Monga SP. Zonation, Zonation, Zonation: The Real Estate of the Liver. Annu Rev Pathol. 2026;21(1):185-212. doi: 10.1146/annurev-pathmechdis-042624-091820

 

  1. Fujiwara N, Kimura G, Nakagawa H. Emerging Roles of Spatial Transcriptomics in Liver Research. Semin Liver Dis. 2024;44(2):115-132. doi: 10.1055/a-2299-7880

 

  1. Saviano A, Henderson NC, Baumert TF. Single-cell genomics and spatial transcriptomics: Discovery of novel cell states and cellular interactions in liver physiology and disease biology. J Hepatol. 2020;73(5):1219-1230. doi: 10.1016/j.jhep.2020.06.004

 

  1. Wang S, Xu B, Liang J, et al. Spatial Transcriptomic Study Reveals Heterogeneous Metabolic Adaptation and a Role of Pericentral PPARα/CAR/Ces2a Axis During Fasting in Mouse Liver. Adv Sci. 2024;11(41):e2405240. doi: 10.1002/advs.202405240

 

  1. Gu PY, Xin JX, Yin KL, Zhou CX, Zhang R, Shao SS. [Biological characteristics of liver zonation and its role in disease and aging]. Zhonghua Gan Zang Bing Za Zhi. Jun 20 2025;33(6):601-606. doi: 10.3760/cma.j.cn501113-20241010-00532

 

  1. Andrews TS, Atif J, Liu JC, et al. Single-Cell, Single-Nucleus, and Spatial RNA Sequencing of the Human Liver Identifies Cholangiocyte and Mesenchymal Heterogeneity. Hepatol Commun. 2022;6(4):821-840. doi: 10.1002/hep4.1854

 

  1. Watson BR, Paul B, Rahman RU, et al. Spatial transcriptomics of healthy and fibrotic human liver at single-cell resolution. Nat Commun. 2025;16(1):319. doi: 10.1038/s41467-024-55325-4

 

  1. Paolini E, Longo M, Meroni M, Dongiovanni P. Hepatic Zonation in MASLD: Old Question, New Challenge in the Era of Spatial Omics. Int J Mol Sci. 2025;26(21). doi: 10.3390/ijms262110701

 

  1. Li JZ, Yang L, Xiao MX, et al. Spatial and Single-Cell Transcriptomics Reveals the Regional Division of the Spatial Structure of MASH Fibrosis. Liver Int. 2025;45(4):e16125. doi: 10.1111/liv.16125

 

  1. Liu J, Xiong S, Zhao Y, et al. Unraveling the multifaceted landscape of hepatocellular carcinoma evolution: From pivotal genetic drivers to therapeutic horizons. Biochem Pharmacol. 2025;242(Pt 2):117229. doi: 10.1016/j.bcp.2025.117229

 

  1. Ryaboshapkina M, Azzu V. Sample size calculation for a NanoString GeoMx spatial transcriptomics experiment to study predictors of fibrosis progression in non-alcoholic fatty liver disease. Sci Rep. 2023;13(1):8943. doi: 10.1038/s41598-023-36187-0

 

  1. Gui M, Huang S, Li S, et al. Integrative single-cell transcriptomic analyses reveal the cellular ontological and functional heterogeneities of primary and metastatic liver tumors. J Transl Med. 2024;22(1):206. doi: 10.1186/s12967-024-04947-9

 

  1. Vu H, Sun Y, Xiong Z, et al. Progressive fibrosis in human MASLD is associated with spatially linked transcriptomic signatures of metabolic reprogramming and senescence. JHEP Rep. 2026;8(2):101657. doi: 10.1016/j.jhepr.2025.101657

 

  1. Zhou Y, Zhao Y, Carbonaro M, et al. Perturbed liver gene zonation in a mouse model of non-alcoholic steatohepatitis. Metabolism. 2024;154:155830. doi: 10.1016/j.metabol.2024.155830

 

  1. Chung BK, Øgaard J, Reims HM, Karlsen TH, Melum E. Spatial transcriptomics identifies enriched gene expression and cell types in human liver fibrosis. Hepatol Commun. 2022;6(9):2538-2550. doi: 10.1002/hep4.2001

 

  1. Chen S, Lu Z, Zhao Y, et al. Myeloid-Mas Signaling Modulates Pathogenic Crosstalk among MYC(+) CD63(+) Endothelial Cells, MMP12(+) Macrophages, and Monocytes in Acetaminophen-Induced Liver Injury. Adv Sci. 2024;11(16):e2306066. doi: 10.1002/advs.202306066

 

  1. Yu YP, Obert C, Ren BG, et al. Deep spatial sequencing revealing differential immune responses in human hepatocellular carcinoma. Front Cell Dev Biol. 2025;13:1600129. doi: 10.3389/fcell.2025.1600129

 

  1. Jing SY, Liu D, Feng N, et al. Spatial multiomics reveals a subpopulation of fibroblasts associated with cancer stemness in human hepatocellular carcinoma. Genome Med. 2024;16(1):98. doi: 10.1186/s13073-024-01367-8

 

  1. Li Y, Huan C, Sun H, et al. Spatial Transcriptomics and snRNA-seq Expose CAF Niches Orchestrating Dual Stromal-Immune Barriers in Hepatocellular Carcinoma. Adv Sci. 2025;12(48):e14661. doi: 10.1002/advs.202514661

 

  1. Riaz T, Rasheed S, Zubair M. Integrative genomic and transcriptomic profiling identifies HSPA5 as a central player in hepatocellular carcinoma pathogenesis. Comput Biol Chem. 2026;120(Pt 2):108722. doi: 10.1016/j.compbiolchem.2025.108722

 

  1. Brazovskaja A, Gomes T, Holtackers R, et al. Cell atlas of the regenerating human liver after portal vein embolization. Nat Commun. 2024;15(1):5827. doi: 10.1038/s41467-024-49236-7

 

  1. Singh-Varma A, Shah AM, Liu S, Zamora R, Monga SP, Vodovotz Y. Defining spatiotemporal gene modules in liver regeneration using Analytical Dynamic Visual Spatial Omics Representation (ADViSOR). Hepatol Commun. 2023;7(11). doi: 10.1097/hc9.0000000000000289

 

  1. Tian H, Rajbhandari P, Tarolli J, et al. Multimodal mass spectrometry imaging identifies cell-type-specific metabolic and lipidomic variation in the mammalian liver. Dev Cell. 2024;59(7):869-881.e6. doi: 10.1016/j.devcel.2024.01.025

 

  1. Kang SWS, Cunningham RP, Miller CB, et al. A spatial map of hepatic mitochondria uncovers functional heterogeneity shaped by nutrient-sensing signaling. Nat Commun. 2024;15(1):1799. doi: 10.1038/s41467-024-45751-9

 

  1. Qian J, Shao X, Bao H, et al. Identification and characterization of cell niches in tissue from spatial omics data at single-cell resolution. Nat Commun. 2025;16(1):1693. doi: 10.1038/s41467-025-57029-9

 

  1. Liu Z, Wu D, Zhai W, Ma L. SONAR enables cell type deconvolution with spatially weighted Poisson-Gamma model for spatial transcriptomics. Nat Commun. 2023;14(1):4727. doi: 10.1038/s41467-023-40458-9

 

  1. Ramachandran P, Dobie R, Wilson-Kanamori JR, et al. Resolving the fibrotic niche of human liver cirrhosis at single-cell level. Nature. 2019;575(7783):512-518. doi: 10.1038/s41586-019-1631-3

 

  1. Banales JM, Huebert RC, Karlsen T, Strazzabosco M, LaRusso NF, Gores GJ. Cholangiocyte pathobiology. Nat Rev Gastroenterol Hepatol. 2019;16(5):269-281. doi: 10.1038/s41575-019-0125-y

 

  1. Aliya S, Lee H, Alhammadi M, Umapathi R, Huh YS. An Overview on Single-Cell Technology for Hepatocellular Carcinoma Diagnosis. Int J Mol Sci. 2022;23(3). doi: 10.3390/ijms23031402

 

  1. Tejima K, Kozawa S, Sato TN. Cell type-specific weighting-factors to solve solid organs-specific limitations of single cell RNA-sequencing. PLoS Genet. 2024;20(11):e1011436. doi: 10.1371/journal.pgen.1011436

 

  1. Zhang L, Chen D, Song D, et al. Clinical and translational values of spatial transcriptomics. Signal Transduct Target Ther. 2022;7(1):111. doi: 10.1038/s41392-022-00960-w

 

  1. Zhang Y, Yu HJ, Yan ZH, et al. Integrating Graph Convolutional Networks for Missing Gene Expression Imputation. IEEE Trans Comput Biol Bioinform. 2025;22(6):2955-2963. doi: 10.1109/tcbbio.2025.3605719

 

  1. Avşar G, Pir P. A comparative performance evaluation of imputation methods in spatially resolved transcriptomics data. Mol Omics. 2023;19(2):162-173. doi: 10.1039/d2mo00266c

 

  1. Upadhyay J, Nandave M, Thajudeen KY, Rashid S, Ansari MN. Molecular Mechanisms and Therapeutic Targeting of Heat Shock Proteins (HSPs) in Cardiovascular Disorders. Front Biosci (Landmark Ed). 2025;30(5):27324. doi: 10.31083/fbl27324

 

  1. Barrows KM, Porat-Shliom N. Hot Zones for Liver Cancer: Metabolic Zonation, Ferroptosis, and the Origins of HCC. Cancer Res. 2026;86(6):1347-1350. doi: 10.1158/0008-5472.Can-25-5839

 

  1. França GS, Baron M, King BR, et al. Cellular adaptation to cancer therapy along a resistance continuum. Nature. 2024;631(8022):876-883. doi: 10.1038/s41586-024-07690-9

 

  1. Jia WT, Xiang S, Zhang JB, et al. Jiedu recipe, a compound Chinese herbal medicine, suppresses hepatocellular carcinoma metastasis by inhibiting the release of tumor-derived exosomes in a hypoxic microenvironment. J Integr Med. 2024;22(6):696-708. doi: 10.1016/j.joim.2024.10.002

 

  1. Gemin O, Gluc M, Rosa H, et al. Ribosomes hibernate on mitochondria during cellular stress. Nat Commun. 2024;15(1):8666. doi: 10.1038/s41467-024-52911-4

 

  1. Yang Y, Li W, Liu C, et al. Single-cell RNA seq identifies Plg- R(KT)-PLG as signals inducing phenotypic transformation of scar-associated macrophage in liver fibrosis. Biochim Biophys Acta Mol Basis Dis. 2023;1869(6):166754. doi: 10.1016/j.bbadis.2023.166754

 

  1. Lee KJ, An S, Kim MY, et al. Hepatic TREM2(+) macrophages express matrix metalloproteinases to control fibrotic scar formation. Immunol Cell Biol. 2023;101(3):216-230. doi: 10.1111/imcb.12616

 

  1. Fabre T, Barron AMS, Christensen SM, et al. Identification of a broadly fibrogenic macrophage subset induced by type 3 inflammation. Sci Immunol. 2023;8(82):eadd8945. doi: 10.1126/sciimmunol.add8945

 

  1. Bhattacharya M, Ramachandran P. Immunology of human fibrosis. Nat Immunol. 2023;24(9):1423-1433. doi: 10.1038/s41590-023-01551-9

 

  1. Ye C, Zhu J, Wang J, et al. Single-cell and spatial transcriptomics reveal the fibrosis-related immune landscape of biliary atresia. Clin Transl Med. 2022;12(11):e1070. doi: 10.1002/ctm2.1070

 

  1. Li X, Liu S, Li T, et al. Inflammatory factor CCL2 enhances the interaction between monocyte-macrophage cells and liver parenchymal cells to promote liver inflammation and fibrosis in biliary atresia. BMC Pediatr. 2025;25(1):643. doi: 10.1186/s12887-025-05984-z

 

  1. Liu Z, Xiang H, Xiang D, et al. Revealing potential anti-fibrotic mechanism of Ganxianfang formula based on RNA sequence. Chin Med. 2022;17(1):23. doi: 10.1186/s13020-022-00579-7

 

  1. Zhang S, Dong H, Jin X, Sun J, Li Y. The multifaceted roles of macrophages in the transition from hepatitis to hepatocellular carcinoma: From mechanisms to therapeutic strategies. Biochim Biophys Acta Mol Basis Dis. 2025;1871(3):167676. doi: 10.1016/j.bbadis.2025.167676

 

  1. Wang W, Li S, Liu Y, et al. Macrophage heterogeneity in liver fibrosis. Front Immunol. 2025;16:1639455.doi: 10.3389/fimmu.2025.1639455

 

  1. Dai H, Zhu C, Huai Q, et al. Chimeric antigen receptor-modified macrophages ameliorate liver fibrosis in preclinical models. J Hepatol. 2024;80(6):913-927. doi: 10.1016/j.jhep.2024.01.034

 

  1. Xu K, Kessler A, Nichetti F, et al. Lymphotoxin beta-activated LTBR/NIK/RELB axis drives proliferation in cholangiocarcinoma. Liver Int. 2024;44(11):2950-2963. doi: 10.1111/liv.16069

 

  1. Zhang SH, Yang MY, Xu YN, et al. Total astragalus saponins enhance the anti-liver fibrosis efficacy of Numb-overexpressed hUC-MSCs through stabilizing the Numb-p53 axis. J Ethnopharmacol. 2026;358:120980. doi: 10.1016/j.jep.2025.120980

 

  1. Condorelli AG, Nobili R, Muglia A, et al. Gamma-Secretase Inhibitors Downregulate the Profibrotic NOTCH Signaling Pathway in Recessive Dystrophic Epidermolysis Bullosa. J Invest Dermatol. 2024;144(7):1522-1533.e10. doi: 10.1016/j.jid.2023.10.045

 

  1. Sasidharan K, Caddeo A, Jamialahmadi O, et al. IL32 downregulation lowers triglycerides and type I collagen in di-lineage human primary liver organoids. Cell Rep Med. 2024;5(1):101352. doi: 10.1016/j.xcrm.2023.101352

 

  1. Gu SM, Lee YS, Yoon DY, et al. Multifaceted role of interleukin-32 in inflammatory diseases and cancer. Biomed Pharmacother. 2026;194:118931. doi: 10.1016/j.biopha.2025.118931

 

  1. Xu C, Su R, Song Y, et al. Integrating spatial transcriptomics and single-cell RNA-seq dissects immune microenvironment in fatty liver regeneration. Clin Transl Med. 2025;15(6):e70365. doi: 10.1002/ctm2.70365

 

  1. Wu R, Guo W, Qiu X, et al. Comprehensive analysis of spatial architecture in primary liver cancer. Sci Adv. 2021;7(51):eabg3750. doi: 10.1126/sciadv.abg3750

 

  1. Nikopoulou C, Kleinenkuhnen N, Parekh S, et al. Spatial and single-cell profiling of the metabolome, transcriptome and epigenome of the aging mouse liver. Nat Aging. 2023;3(11):1430-1445. doi: 10.1038/s43587-023-00513-y

 

  1. Shu L, Li L, Jiang YQ, Yan J. Advances in membrane-tethered NAC transcription factors in plants. Plant Sci. 2024;342:112034. doi: 10.1016/j.plantsci.2024.112034

 

  1. Lin P, Yan X, Jing S, et al. Single-cell and spatially resolved transcriptomics for liver biology. Hepatology. 2024;80(3):698-720. doi: 10.1097/hep.0000000000000387

 

  1. Hildebrandt F, Andersson A, Saarenpää S, et al. Spatial Transcriptomics to define transcriptional patterns of zonation and structural components in the mouse liver. Nat Commun. 2021;12(1):7046. doi: 10.1038/s41467-021-27354-w

 

  1. Cordier P, Hirsch TZ, Caruso S, et al. Intratumour ploidy heterogeneity and clonal evolution in hepatocellular carcinoma. J Hepatol. 2026;84(4):776-792. doi: 10.1016/j.jhep.2025.11.015

 

  1. Chitra U, Arnold BJ, Sarkar H, et al. Mapping the topography of spatial gene expression with interpretable deep learning. Nat Methods. 2025;22(2):298-309. doi: 10.1038/s41592-024-02503-3

 

  1. Tarhini AA, El Naqa I. Artificial Intelligence for Multiscale Spatial Analysis in Oncology: Current Applications and Future Implications. Int J Mol Sci. 2025;26(16). doi: 10.3390/ijms26168002

 

  1. Rosenberger FA, Thielert M, Strauss MT, et al. Spatial single-cell mass spectrometry defines zonation of the hepatocyte proteome. Nat Methods. 2023;20(10):1530-1536. doi: 10.1038/s41592-023-02007-6

 

  1. McKenzie M, Irac SE, Chen Z, et al. Integrative spatial omics and artificial intelligence: transforming cancer research with omics data and AI. Semin Cancer Biol. 2026;119:65-82. doi: 10.1016/j.semcancer.2026.01.002

 

  1. Massalha H, Bahar Halpern K, Abu-Gazala S, et al. A single cell atlas of the human liver tumor microenvironment. Mol Syst Biol. 2020;16(12):e9682. doi: 10.15252/msb.20209682

 

  1. Liang W, Zhu Z, Xu D, et al. The burgeoning spatial multi-omics in human gastrointestinal cancers. PeerJ. 2024;12:e17860. doi: 10.7717/peerj.17860

 

  1. Wu J, Liu W, Qiu X, et al. A Noninvasive Approach to Evaluate Tumor Immune Microenvironment and Predict Outcomes in Hepatocellular Carcinoma. Phenomics. 2023;3(6):549-564. doi: 10.1007/s43657-023-00136-8

 

  1. Hwang JE, Jeon M, Yim H, et al. Collagenase-Functionalized Liposomes Overcome Stromal Barriers in Pancreatic Cancer. ACS Nano. 2026;20(8):7184-7204. doi: 10.1021/acsnano.5c20618

 

  1. Rance N. How single-cell transcriptomics provides insight on hepatic responses to TCDD. Curr Opin Toxicol. 2023;36. doi: 10.1016/j.cotox.2023.100441

 

  1. Peroni E, Calistri E, Amato R, Gottardi M, Rosato A. Spatial-transcriptomic profiling: a new lens for understanding myelofibrosis pathophysiology. Cell Commun Signal. 2024;22(1):510. doi: 10.1186/s12964-024-01877-3

 

  1. Huang Y, Lei L, Long J, et al. Spatially Targeted PD-L1 Blockade for Restoring Exhausted Cytotoxic T Lymphocyte Rejuvenation to Potentiate Multimodal-Immune Synergistic Therapies for Breast Cancer Treatment. Small. 2025;21(27):e2410953. doi: 10.1002/smll.202410953

 

  1. Hincapie R, Bhattacharya S, Baksh MM, et al. Multivalent Targeting of the Asialoglycoprotein Receptor by Virus-Like Particles. Small. 2023;19(52):e2304263. doi: 10.1002/smll.202304263

 

  1. Martini T, Naef F, Tchorz JS. Spatiotemporal Metabolic Liver Zonation and Consequences on Pathophysiology. Annu Rev Pathol. 2023;18:439-466. doi: 10.1146/annurev-pathmechdis-031521-024831

 

  1. Fukumoto K, Hikita H, Saito Y, et al. Liver Sinusoidal Endothelial Cells Promote Metabolic Dysfunction-associated Steatohepatitis Progression via Interleukin- 1R1-mediated Chemokine Production Induced by Macrophage-derived Interleukin-1β. Cell Mol Gastroenterol Hepatol. 2026;20(4):101698. doi: 10.1016/j.jcmgh.2025.101698
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Eurasian Journal of Medicine and Oncology, Electronic ISSN: 2587-196X Print ISSN: 2587-2400, Published by AccScience Publishing
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