GATA2 deficiency exacerbates chronic liver injury via disrupting hepatocyte death-regeneration balance: Clinical, histopathological, and molecular evidence

doi:10.4252/wjsc.v18.i2.112940

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Feb 26, 2026 (publication date) through Feb 17, 2026

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World Journal of Stem Cells

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1948-0210

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

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©Author(s) (or their employer(s)) 2026. No commercial re-use. See Permissions. Published by Baishideng Publishing Group Inc.

World J Stem Cells. Feb 26, 2026; 18(2): 112940
Published online Feb 26, 2026. doi: 10.4252/wjsc.v18.i2.112940

GATA2 deficiency exacerbates chronic liver injury via disrupting hepatocyte death-regeneration balance: Clinical, histopathological, and molecular evidence

Yun-Fen Chen, Su-Qun Li, Jing Zhang, Wen-Ting Ma, Ying Zhou, Jian-Xu Rao, Yu Yi, Qi-Jiao Cheng, Wei-Wei Zhong, Huan Chen, Ying-Hua Chen, Ya-Wen Luo, Yi-Huai He

Yun-Fen Chen, Su-Qun Li, Jing Zhang, Ying Zhou, Jian-Xu Rao, Yu Yi, Qi-Jiao Cheng, Ying-Hua Chen, Ya-Wen Luo, Yi-Huai He, Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China

Wen-Ting Ma, State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Key Laboratory of Molecular Biology for Endemic Diseases, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi 830000, Xinjiang Uygur Autonomous Region, China

Wei-Wei Zhong, Department of Infectious Diseases, Jingmen Central Hospital, Jingmen Central Hospital Affiliated to Jingchu University of Technology, Jingmen 448000, Hubei Province, China

Huan Chen, Department of Endocrinology, Taoxi Branch of Zunyi First People’s Hospital, Zunyi 563000, Guizhou Province, China

Co-first authors: Yun-Fen Chen and Su-Qun Li.

Co-corresponding authors: Ya-Wen Luo and Yi-Huai He.

Author contributions: Chen YF, Li SQ, Zhang J, Ma WT, Zhou Y, Rao JX, Yi Y, Cheng QJ, Zhong WW, Chen H, Chen YH, Luo YW, and He YH made substantial contributions to this study. Chen YF and Li SQ contributed equally to this work and are co-first authors; Chen YF, Li SQ, Zhang J, Rao JX, Yi Y, Chen H, and Chen YH collected the medical history data; Chen YF, Zhang J, Zhou Y, Rao JX, Yi Y, Cheng QJ, Zhong WW, and Chen H analyzed the medical history data; Chen YF, Li SQ, Yi Y, Cheng QJ, Chen YH, Luo YW, and He YH conceived and designed the content of the article; Chen YF, Li SQ, and He YH wrote the initial manuscript; Cheng QJ, Zhong WW, Chen YH, and He YH revised the manuscript; He YH, and Luo YW had primary responsibility for final content; Luo YW and He YH contributed equally to this work and are co-corresponding authors. All authors read and approved the final manuscript.

Supported by the Science and Technology Planning Projects of Guizhou Province, No. QKHJC-MS(2025)384; Health Research Project of Guizhou Province, No. gzwkj2023121; Science and Technology Research Foundation of Zunyi City, No. ZSKHHZ(2023)470; WBE Liver Fibrosis Foundation, No. CFHPC2025028; and Beijing Liver and Gallbladder Mutual Aid Public Welfare Foundation Artificial Liver Special Fund, No. iGandanF-1082024-RGG018.

Institutional review board statement: The experiments involving human liver cells were approved by the Medical Ethics Committee of Zunyi Medical University [Approval No. (2023)1-172] and was conducted in compliance with the Declaration of Helsinki. Written informed consent was obtained from each participant.

Institutional animal care and use committee statement: All procedures involving experimental animals strictly adhered to laboratory animal welfare ethics guidelines and were approved by the Laboratory Animal Ethics Committee of Zunyi Medical University (Approval No. ZMU22-2303-029).

Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.

ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.

Data sharing statement: The data supporting the findings of this study are available from the corresponding author upon reasonable request.

Corresponding author: Yi-Huai He, MD, Department of Infectious Diseases, Affiliated Hospital of Zunyi Medical University, No. 201 Dalian Street, Zunyi 563000, Guizhou Province, China. 993565989@qq.com

Received: August 11, 2025
Revised: October 23, 2025
Accepted: December 19, 2025
Published online: February 26, 2026
Processing time: 187 Days and 14.1 Hours

Abstract

BACKGROUND

GATA-binding protein 2 (GATA2) is a critical transcription factor that plays an essential role in maintaining the stemness of hematopoietic stem cells. Mutations in GATA2 are recognized as disease-causing mutations for aplastic anemia (AA) and myelodysplastic syndromes; however, the mechanisms linking these mutations to chronic liver injury (CLI) (e.g., cirrhosis) remain elusive.

AIM

To investigate the molecular mechanisms through which GATA2 deficiency promotes CLI.

METHODS

Whole genome sequencing was performed to identify loss-of-function mutations in GATA2 in a 55-year-old female patient who was suspected of and later diagnosed with AA and developed cirrhosis one year post-diagnosis. After establishing the genetic association between GATA2 mutations and cirrhosis through clinical case analysis, liver injury murine and hepatocyte models were developed to characterize GATA2 expression in response to liver injury. rAAV8-TBG-Gata2-shRNA-mediated liver-specific Gata2 knockdown was employed to elucidate the role of GATA2 in exacerbating liver injury.

RESULTS

The patient presented with a three-year medical history of dizziness, fatigue, and thrombocytopenia. Following conventional treatment, she developed severe fatigue, abdominal distension, and jaundice, indicative of liver disease. Multimodal evaluations, including bone marrow biopsy, flow cytometry, liver biopsy, and genetic testing, confirmed GATA2 mutation-associated AA complicated by cirrhosis. Experimental studies in cellular and animal models demonstrated compensatory upregulation of hepatocyte GATA2 in response to endoplasmic reticulum stress and oxidative stress. Mechanistically, liver-specific Gata2 knockdown exacerbated hepatocyte apoptosis, necroptosis, ferroptosis, and impaired regeneration. Furthermore, Gata2 knockdown suppressed the adaptive unfolded protein response, attenuated the antioxidant response, and inhibited fatty acid β-oxidation.

CONCLUSION

GATA2 deficiency drives the CLI by disrupting the hepatocyte death-regeneration balance.

Keywords: GATA2 deficiency; Aplastic anemia; Chronic liver injury; Hepatocyte death-regeneration balance; Unfolded protein response; Antioxidant response

Core Tip: GATA-binding protein 2 (GATA2) is known to play a crucial role in maintaining the stemness of hematopoietic stem cells, but its involvement in chronic liver injury (CLI), such as cirrhosis, remains unclear. Through an investigation into clinical cases and experimental models, this study demonstrates that GATA2 deficiency drives the progression of CLI by disrupting the hepatocyte death-regeneration balance. The findings suggest that GATA2 mutations contribute not only to aplastic anemia pathogenesis but also act as a causative factor in CLI, highlighting its potential as a therapeutic target for managing liver complications in aplastic anemia patients.