Single-cell transcriptome sequencing reveals hepatocyte heterogeneity in response to radiation-induced liver injury and regeneration
Abstract
Background and purpose Radiation-induced liver injury (RILI) presents a significant constraint on radiotherapy efficacy for hepatic malignancies, yet its underlying mechanisms remain poorly defined. Materials and methods Employing integrated single-cell and single-nucleus RNA sequencing in a rat model receiving 3/4 vol partial liver irradiation (25 Gy), combined with proteomic profiling of human liver tissues, we delineated the spatiotemporal dynamics of hepatocyte responses to RILI. Results Hepatocyte subpopulations exhibited a compartmentalized division of labor: midzonal (zone 2) hepatocytes were characterized by transient proliferation in conjunction with coagulation factors (Fga/Fgb/Fgg) and ERK signaling, whereas periportal and pericentral (zone 1and 3) hepatocytes were characterized by p53-mediated cell cycle restraint and metabolic adaptation involving PPARα-YAP1-TEAD1 signaling. Trajectory analysis supported zone 2 hepatocytes as the primary source for repopulating damaged zone 1/3 compartments, with periportal regions (zone 1) replenishing first. Notably, pericentral (zone 3) hepatocytes demonstrated heightened vulnerability, manifesting late-stage hypertrophy and S-phase arrest. Interzonal crosstalk, including VEGFA-KDR signaling from zone 1/3 that was associated with zone 2 vascular remodeling and HGF-MET/GAS6-MERTK pathways that may coordinate regeneration and survival, may further contribute to repair. Critically, proteomic profiling of irradiated human liver tissues validated conserved activation of p53, coagulation, ERK, and PPAR/YAP pathways. Conclusion Our findings unveil a sophisticated spatial paradigm of liver regeneration following radiation injury, wherein spatially partitioned hepatocyte subpopulations deploy compartmentalized repair programs to balance proliferative efficiency and metabolic adaptation, suggesting potential new targets for therapeutic intervention against RILI.
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clusterProfiler: an R Package for Comparing Biological Themes Among Gene Clusters
Yu, G., Wang, L.-G., Han, Y., & He, Q.-Y. (2012) · OMICS: A Journal of Integrative Biology · doi:10.1089/omi.2011.0118 · Cited by 36,259 · see citing works
Comprehensive Integration of Single-Cell Data
Stuart, T., Butler, A., Hoffman, P., Hafemeister, C., Papalexi, E., Mauck, W. M., Hao, Y., Stoeckius, M., Smibert, P., & Satija, R. (2019) · Cell · doi:10.1016/j.cell.2019.05.031 · Cited by 15,453 · see citing works
Fast, sensitive and accurate integration of single-cell data with Harmony
Korsunsky, I., Millard, N., Fan, J., Slowikowski, K., Zhang, F., Wei, K., Baglaenko, Y., Brenner, M., Loh, P.-R., & Raychaudhuri, S. (2019) · Nature Methods · doi:10.1038/s41592-019-0619-0 · Cited by 10,488 · see citing works
SCANPY: large-scale single-cell gene expression data analysis
Wolf, F. A., Angerer, P., & Theis, F. J. (2018) · Genome Biology · doi:10.1186/s13059-017-1382-0 · Cited by 8,881 · see citing works
Trapnell, C., Cacchiarelli, D., Grimsby, J., Pokharel, P., Li, S., Morse, M., Lennon, N. J., Livak, K. J., Mikkelsen, T. S., & Rinn, J. L. (2014) · Nature Biotechnology · doi:10.1038/nbt.2859 · Cited by 7,314 · see citing works
McGinnis, C. S., Murrow, L. M., & Gartner, Z. J. (2019) · Cell Systems · doi:10.1016/j.cels.2019.03.003 · Cited by 4,521 · see citing works
Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1
Barbie, D. A., Tamayo, P., Boehm, J. S., Kim, S. Y., Moody, S. E., Dunn, I. F., Schinzel, A. C., Sandy, P., Meylan, E., Scholl, C., et al. (2009) · Nature · doi:10.1038/nature08460 · Cited by 3,869 · see citing works
Slingshot: cell lineage and pseudotime inference for single-cell transcriptomics
Street, K., Risso, D., Fletcher, R. B., Das, D., Ngai, J., Yosef, N., Purdom, E., & Dudoit, S. (2018) · BMC Genomics · doi:10.1186/s12864-018-4772-0 · Cited by 3,159 · see citing works
Generalizing RNA velocity to transient cell states through dynamical modeling
Bergen, V., Lange, M., Peidli, S., Wolf, F. A., & Theis, F. J. (2020) · Nature Biotechnology · doi:10.1038/s41587-020-0591-3 · Cited by 2,951 · see citing works
Mechanisms and disease consequences of nonalcoholic fatty liver disease
Loomba, R., Friedman, S. L., & Shulman, G. I. (2021) · Cell · doi:10.1016/j.cell.2021.04.015 · Cited by 2,002 · see citing works
Trefts, E., Gannon, M., & Wasserman, D. H. (2017) · Current Biology · doi:10.1016/j.cub.2017.09.019 · Cited by 1,452 · see citing works
Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas
Knijnenburg, T., Wang, L., Zimmermann, M. T., Chambwe, N., Gao, G. F., Cherniack, A. D., Fan, H., Shen, H., Way, G. P., Greene, C. S., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.03.076 · Cited by 1,126 · see citing works
Self-citationA new gene set identifies senescent cells and predicts senescence-associated pathways across tissues
Saul, D., Kosinsky, R. L., Atkinson, E. J., Doolittle, M. L., Zhang, X., LeBrasseur, N. K., Pignolo, R. J., Robbins, P. D., Niedernhofer, L. J., Ikeno, Y., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-32552-1 · Cited by 1,060 · see citing works
Single-cell spatial reconstruction reveals global division of labour in the mammalian liver
Halpern, K. B., Shenhav, R., Matcovitch-Natan, O., Tóth, B., Lemze, D., Golan, M., Massasa, E. E., Baydatch, S., Landen, S., Moor, A. E., et al. (2017) · Nature · doi:10.1038/nature21065 · Cited by 1,059 · see citing works
Liver regeneration: biological and pathological mechanisms and implications
Michalopoulos, G. K., & Bhushan, B. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-020-0342-4 · Cited by 998 · see citing works
Hippo–YAP/TAZ signalling in organ regeneration and regenerative medicine
Moya, I. M., & Halder, G. (2019) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-018-0086-y · Cited by 981 · see citing works
Triggering and resolution of inflammation in NASH
Schuster, S., Cabrera, D., Arrese, M., & Feldstein, A. E. (2018) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-018-0009-6 · Cited by 943 · see citing works
Alcoholic liver disease: mechanisms of injury and targeted treatment
Louvet, A., & Mathurin, P. (2015) · Nature Reviews Gastroenterology &Hepatology · doi:10.1038/nrgastro.2015.35 · Cited by 820 · see citing works
Decontamination of ambient RNA in single-cell RNA-seq with DecontX
Yang, S., Corbett, S. E., Koga, Y., Wang, Z., Johnson, W. E., Yajima, M., & Campbell, J. D. (2020) · Genome Biology · doi:10.1186/s13059-020-1950-6 · Cited by 635 · see citing works
Interplay between YAP/TAZ and Metabolism
Koo, J. H., & Guan, K. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.07.010 · Cited by 468 · see citing works
Hypertrophy and Unconventional Cell Division of Hepatocytes Underlie Liver Regeneration
Miyaoka, Y., Ebato, K., Kato, H., Arakawa, S., Shimizu, S., & Miyajima, A. (2012) · Current Biology · doi:10.1016/j.cub.2012.05.016 · Cited by 461 · see citing works
Liver ischaemia–reperfusion injury: a new understanding of the role of innate immunity
Hirao, H., Nakamura, K., & Kupiec‐Weglinski, J. W. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-021-00549-8 · Cited by 375 · see citing works
TAM receptors, Gas6, and protein S: roles in inflammation and hemostasis
van der Meer, J. H. M., van der Poll, T., & Veer, C. V. ′. (2014) · Blood · doi:10.1182/blood-2013-09-528752 · Cited by 341 · see citing works
Fibrosis and alcohol-related liver disease
Lackner, C., & TINIAKOS, D. G. (2019) · Journal of Hepatology · doi:10.1016/j.jhep.2018.12.003 · Cited by 326 · see citing works
Drug induced liver injury: an update
García‐Cortés, M., Robles‐Díaz, M., Stephens, C. M., Ortega‐Alonso, A., Lucena, M. I., & Andrade, R. J. (2020) · Archives of Toxicology · doi:10.1007/s00204-020-02885-1 · Cited by 302 · see citing works
Liver homeostasis is maintained by midlobular zone 2 hepatocytes
Wei, Y., Wang, Y. G., Jia, Y., Li, L., Yoon, J., Zhang, S., Wang, Z., Zhang, Y., Zhu, M., Sharma, T., et al. (2021) · Science · doi:10.1126/science.abb1625 · Cited by 292 · see citing works
Self-citationLiang, S., Zhu, X., Xu, Z., et al. (2006) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/j.ijrobp.2005.12.031 · Cited by 267 · see citing works
Self-citationThe spatiotemporal program of zonal liver regeneration following acute injury
Ben-Moshe, S., Veg, T., Manco, R., Dan, S., Papinutti, D., Lifshitz, A., Kolodziejczyk, A. A., Bahar Halpern, K., Elinav, E., & Itzkovitz, S. (2022) · Cell Stem Cell · doi:10.1016/j.stem.2022.04.008 · Cited by 224 · see citing works
YAP/TEAD–Mediated Transcription Controls Cellular Senescence
Xie, Q., Chen, J., Han, F., Peng, S., Adams, U., Bai, Y., Huang, L., Li, J., Huang, J., Meng, S., et al. (2013) · Cancer Research · doi:10.1158/0008-5472.can-12-3793 · Cited by 172 · see citing works
Paris, J., & Henderson, N. C. (2022) · Hepatology · doi:10.1002/hep.32408 · Cited by 167 · see citing works
Radiation-Induced Liver Disease and Modern Radiotherapy
Koay, E. J., Owen, D., & Das, P. (2018) · Seminars in Radiation Oncology · doi:10.1016/j.semradonc.2018.06.007 · Cited by 162 · see citing works
HGF/c-Met: A Key Promoter in Liver Regeneration
Zhao, Y., Ye, W., Wang, Y., & Chen, W. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.808855 · Cited by 151 · see citing works
Duan, J., Ruan, B., Song, P., Fang, Z., Yue, Z., Liu, J., Dou, G., Han, H., & Wang, L. (2021) · Hepatology · doi:10.1002/hep.32209 · Cited by 145 · see citing works
Dorota Dworakowska, B., Wlodek, E., Leontiou, C. A., et al. (2009) · Endocrine Related Cancer · doi:10.1677/erc-09-0101 · Cited by 144 · see citing works
Mfsd2a+ hepatocytes repopulate the liver during injury and regeneration
Pu, W., Zhang, H., Huang, X., Tian, X., He, L., Wang, Y., Zhang, L., Liu, Q., Li, Y., Li, Y., et al. (2016) · Nature Communications · doi:10.1038/ncomms13369 · Cited by 136 · see citing works
Su, T., Liang, P., Liang, J., Lu, H., Jiang, H.-Y., Cheng, T., Huang, Y., Tang, Y., & Deng, X. (2017) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/j.ijrobp.2017.02.095 · Cited by 117 · see citing works
Self-citationBae, S. H., Chun, S.-J., Chung, J.-H., Kim, E., Kang, J.-K., Jang, W. I., Moon, J. E., Roquette, I., Mirabel, X., Kimura, T., et al. (2023) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/j.ijrobp.2023.08.015 · Cited by 109 · see citing works
Self-citationYAP‐TEAD mediates PPAR α–induced hepatomegaly and liver regeneration in mice
Fan, S., Gao, Y., Qu, A., Jiang, Y., Li, H., Xie, G., Yao, X., Xiao, Y., Zhu, S., Yagai, T., et al. (2021) · Hepatology · doi:10.1002/hep.32105 · Cited by 109 · see citing works
Yeoh, G. C., Ernst, M., Rose‐John, S., Akhurst, B., Payne, C. J., Long, S., Alexander, W. S., Croker, B. A., Grail, D., & Matthews, V. B. (2007) · Hepatology · doi:10.1002/hep.21535 · Cited by 102 · see citing works
Microscopic and Macroscopic Tumor and Parenchymal Effects of Liver Stereotactic Body Radiotherapy
Olsen, C. C., Welsh, J. W., Kavanagh, B. D., et al. (2008) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/j.ijrobp.2008.07.032 · Cited by 92 · see citing works
Hepatic PPARs: Their Role in Liver Physiology, Fibrosis and Treatment
Zardi, E. M., Navarini, L., Sambataro, G., Piccinni, P., Sambataro, F., Spina, C., & Dobrina, A. (2013) · Current Medicinal Chemistry · doi:10.2174/09298673113209990136 · Cited by 91 · see citing works
Chen, T., Oh, S., Gregory, S., Shen, X., & Diehl, A. M. (2020) · JCI Insight · doi:10.1172/jci.insight.141024 · Cited by 79 · see citing works
Du, S., Chen, G., Yuan, B., Hu, Y., Yang, P., Chen, Y., Zhao, Q., Zhou, J., Fan, J., & Zeng, Z. (2020) · Cellular and Molecular Immunology · doi:10.1038/s41423-020-0395-x · Cited by 70 · see citing works
Chen, Y., Wu, Z., Yuan, B., Dong, Y., Zhang, L., & Zeng, Z. (2018) · Cell Death and Disease · doi:10.1038/s41419-017-0038-z · Cited by 69 · see citing works
Compensatory cellular hypertrophy: the other strategy for tissue homeostasis
Tamori, Y., & Deng, W. (2013) · Trends in Cell Biology · doi:10.1016/j.tcb.2013.10.005 · Cited by 56 · see citing works
Huang, M., Jiao, J., Cai, H., Zhang, Y., Xia, Y., Lin, J., Shang, Z., Qian, Y., Wang, F., Wu, H., et al. (2022) · Hepatology · doi:10.1002/hep.32458 · Cited by 50 · see citing works
Radiation-induced liver disease: beyond DNA damage
Zhou, Y. J., Tang, Y., Liu, S. J., Zeng, P. H., Qu, L., Jing, Q., & Yin, W. J. (2022) · Cell Cycle · doi:10.1080/15384101.2022.2131163 · Cited by 50 · see citing works
Won, M., Park, K. A., Byun, H. S., Kim, Y.-R., Choi, B. L., Hong, J. H., Park, J., Seok, J. H., Lee, Y. H., Cho, C., et al. (2009) · Journal of Hepatology · doi:10.1016/j.jhep.2009.02.027 · Cited by 47 · see citing works
Su, T., Luo, R., Liang, P., et al. (2018) · Radiotherapy and Oncology · doi:10.1016/j.radonc.2018.02.031 · Cited by 44 · see citing works
Self-citationXie, G., Yin, S., Zhang, Z., Qi, D., Wang, X., Kim, D., Yagai, T., Brocker, C. N., Wang, Y., Gonzalez, F. J., et al. (2018) · American Journal Of Pathology · doi:10.1016/j.ajpath.2018.10.009 · Cited by 40 · see citing works
Du, S., Ming, Q., Zeng, Z., Zhou, J., Tan, Y.-S., Zhang, Z., Zeng, H., & Liu, Z. (2010) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/j.ijrobp.2010.06.046 · Cited by 39 · see citing works
Chen, X. (2002) · Developmental Cell · doi:10.1016/s1534-5807(02)00182-x · Cited by 38 · see citing works
Li, L., Zhou, Y., Huang, Y., et al. (2021) · Hepatology International · doi:10.1007/s12072-021-10173-y · Cited by 37 · see citing works
Self-citationA Nonhuman Primate Model of Human Radiation-Induced Venocclusive Liver Disease and Hepatocyte Injury
Yannam, G. R., Han, B., Setoyama, K., et al. (2013) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/j.ijrobp.2013.10.037 · Cited by 35 · see citing works
Microplastic-induced NAFLD: Hepatoprotective effects of nanosized selenium
Shen, Q., Liu, Y. J., Qiu, T. T., k, S. L., & Zhou, D. (2024) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2023.115850 · Cited by 29 · see citing works
Interleukin‐33 facilitates liver regeneration through serotonin‐involved gut‐liver axis
Wen, Y., Emontzpohl, C., Xu, L., Atkins, C. L., Jeong, J., Yang, Y., Kim, K., Wu, C., Akira, S., & Ju, C. (2023) · Hepatology · doi:10.1002/hep.32744 · Cited by 26 · see citing works
Ruz‐Maldonado, I., González, J. T., Zhang, H., Sun, J., Bort, A., Kabir, I., Kibbey, R. G., Suárez, Y., Greif, D. M., & Fernandez-Hernando, C. F. (2024) · Nature Communications · doi:10.1038/s41467-024-45439-0 · Cited by 26 · see citing works
Lu, J., Zhao, Y.-L., Zhang, X.-Q., & Li, L.-J. (2021) · Expert Review of Gastroenterology & Hepatology · doi:10.1080/17474124.2020.1815532 · Cited by 22 · see citing works
Self-citationWang, C., Li, Z., Zhao, B., Wu, Y., Fu, Y., Kang, K., Li, Y., Dong, L., Li, X., Zhang, B., et al. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/6677955 · Cited by 20 · see citing works
The Role of Sirtuin 3 in Radiation-Induced Long-Term Persistent Liver Injury
LoBianco, F. V., Krager, K. J., Carter, G. S., Alam, S., Yuan, Y., Lavoie, É. G., Dranoff, J. A., & Aykin‐Burns, N. (2020) · Antioxidants · doi:10.3390/antiox9050409 · Cited by 16 · see citing works
Landis, C. S., Zhou, H., Liu, L., et al. (2014) · Liver International · doi:10.1111/liv.12507 · Cited by 10 · see citing works
A Dual Role of HGF-ERK Signaling in IL6/HGF-induced Hepatocyte Proliferation
Zhang, J., Wang, S., Yu, J., Li, B., Wang, S., Suo, N., Guo, R. F., & Xie, X. (2025) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2025.101538 · Cited by 8 · see citing works
p21, ccng1, foxo3b, and fbxw7 contribute to p53-dependent cell cycle arrest
Wang, J., Li, Z., Thomas, H. R., Fan, K., Thompson, R. G., Ma, Y., Crossman, D. K., Yoder, B. K., & Parant, J. M. (2025) · iScience · doi:10.1016/j.isci.2025.112558 · Cited by 5 · see citing works
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- Authors
- Li, L., Wu, Q., Lin, Z., Liang, S., Fu, Q., Wei, Y., Wang, B., & Su, T.
- Affiliations
- Guangxi Medical University (CN)
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Wang, Bofei
- Venue
- Radiotherapy and Oncology
- Publisher
- Elsevier BV
- Published
- 2026-01
- Volume
- 214
- Pages
- 111225
- ISSN
- 0167-8140 (ISSN-L)
- OpenAlex
- W4415531814
- Semantic Scholar
- fbd7ca56a8d99d55f73ce302f98a325e71213231
- Cited by
- 1
- References
- 63
- Citations by year
- 2026: 1
- FWCI
- 0.50
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Radiotherapy and Oncology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Bagui Scholars Program of Guangxi Zhuang Autonomous Region
- National Natural Science Foundation of China (82360630, 81903257)
- Guangxi Medical University
- Natural Science Foundation of Guangxi Province (2020GXNSFAA297171)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- radiation-induced liver injury, hepatocyte heterogeneity, liver regeneration, hepatocyte subpopulations, liver zonation, p53, ERK signaling, coagulation factors, HGF/MET pathway, hepatocyte proliferation, metabolic adaptation, radiotherapy toxicity
- MeSH terms
- Animals, Humans, Liver, Liver Regeneration, Male, Radiation Injuries, Hepatocytes, Proteomics, Rats, Single-Cell Analysis, Transcriptome
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