Young-Ri Shim, Hee-Hoon Kim, Min Jeong Kim, Jun-Hee Lee, Kyurae Kim, Sung Eun Choi, Katherine Po Sin Chung, Eunmi Lee, Kwang Woo Lee, Jihyo Byun, Jaewoo Oh, Jae Min Han, Jun Ho Byun, Jong-Eun Park, Won Kim, Young-Sun Lee, Won-Il Jeong
Received April 5, 2026 Accepted June 16, 2026 Published online June 18, 2026
Background/Aims Bone marrow mesenchymal stromal cells (BM-MSCs) exert diverse functions, including supporting alcohol detoxification and providing a niche for monocyte development. However, their role in regulating monocytes during alcohol-related liver disease (ALD) remains unclear. This study investigates how BM-MSCs orchestrate the egress of anti-inflammatory monocytes from BM to the liver in ALD.
Methods Wild-type, leptin receptor (LepR)⁺ BM-MSC-specific Slc7a11 knockout, and natural killer (NK) cell-specific Grm5 knockout mice were fed an ethanol diet for 8 weeks. Tissue analyses were performed using single-cell RNA sequencing (scRNA-seq), immunostaining, and flow cytometry. Blood and liver samples from ALD patients were examined.
Results scRNA-seq revealed a distinct population of BM-derived Ly6Clow hepatic macrophages expressing interleukin-1 receptor 2 (IL-1R2), an IL-1β decoy receptor, in ethanol-fed mice. In the BM, alcohol exposure upregulated the gene expression of alcohol-metabolizing enzymes (Adh1, Aldh2), xCT (Slc7a11), and chemokines (Cxcl9, Cxcl10) in LepR+ BM-MSCs, promoting NK cell recruitment and interferon-γ (IFN-γ) production via metabotropic glutamate receptor 5 (mGluR5) activation. Subsequently, IFN-γ enhanced IL-1R2 expression and suppressed CX3CR1 in neighboring Ly6Clow BM monocytes, facilitating their hepatic migration. LepR+ BM-MSC-specific xCT and NK cell-specific mGluR5 knockout mice exhibited exacerbated liver injury and elevated blood IL-1β levels, while recombinant IL-1R2 administration improved ameliorated ALD in wild-type mice. Consistently, increased IL-1R2 levels were observed in plasma, CD14+CD16+ blood monocytes, and liver tissues of ALD patients.
Conclusions We identified a BM-liver axis in which glutamate released by BM-MSCs activates mGluR5 in BM NK cells, driving IL-1R2+ monocyte migration to the liver and attenuating ALD progression.
Multi-target mechanisms of Banxia Baizhu Tianma Decoction against MASH in a methionine-choline deficient mouse model: insights from a Multi-Omics Investigation Qinying Feng, Lili Gao, Jiewen Shi, Jiekai Hua, Xiaorui Zhao, Jiankang Li, Wei Liu, Qiaoling Yang, Shuling Wang Journal of Ethnopharmacology.2026; 364: 121526. CrossRef
Ursodeoxycholic acid and long COVID in steatotic liver disease: a nationwide cohort study Kyungyeon Jung, Gi-Ae Kim, Jieun Woo, Jin Youn, Eun-Young Choi, Sungho Bea, Ahhyung Choi, Ju Hwan Kim, Heejoon Jang, Dong Hyeon Lee, Sae Kyung Joo, Ju-Young Shin, Won Kim Clinical and Molecular Hepatology.2026; 32(3): 1364. CrossRef
Metabolic Dysfunction-Associated Steatotic Liver Disease as a Risk Factor for Chronic Kidney Disease: A Narrative Review Marcelo do Rego Maciel Souto Maior, Nathália de Lacerda Interaminense Ribeiro, Hannah Vicentini Vitoriano Silva, Edmundo Pessoa Lopes, Emilia Chagas Costa Biomedicines.2025; 13(9): 2162. CrossRef
Chronic alcohol consumption induces the development of alcoholic steatosis in the liver, which is one of the most widespread liver diseases worldwide. During general alcohol metabolism, hepatocytes generate mitochondria- and cytochrome P450 2E1 (CYP2E1)-mediated reactive oxygen species (ROS) whose accumulation elicits activation of the hepatic anti-oxidant system, including glutathione (GSH). However, chronic alcohol consumption decreases GSH generation through cysteine deficiency by suppressing the methionine cycle and trans-sulfuration system, whereas it turns on an alternative defense pathway, such as the xCT transporter, to compensate for GSH shortage. The xCT transporter mediates the uptake of cystine coupled to the efflux of glutamate, leading to an increase in blood glutamate. In response to the elevated glutamate in the liver, the expression of metabotropic glutamate receptor 5 (mGluR5) is up-regulated in hepatic stellate cells (HSCs) along with enhanced production of 2-arachidonoylglycerol, which in turn stimulates cannabinoid receptor 1 (CB1R) on neighboring hepatocytes to increase de novo lipogenesis. On the other hand, blockade of mGluR5 and CB1R attenuates alcoholic steatosis. Interestingly, although the increased expression of CYP2E1-mediated xCT and ROS generation are mainly observed at the perivenous area (zone 3), fat accumulation is mostly detected at hepatic zone 2. To resolve this discrepancy, this review summarizes recent advances on glutamate/mGluR5-derived alcoholic steatosis and zone-dependently different responses to alcohol intake. In addition, the bidirectional loop pathway and its unique metabolic synapse between hepatocytes and HSCs are discussed.
Citations
Citations to this article as recorded by
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 World Journal of Stem Cells.2026;[Epub] CrossRef
NOX1/4 drives hepatic iron and lipid dysregulation, redox imbalance, and inflammation in ethanol-fed mice Linna Yu, Tian He, Pengli Zhang, Xueru Zhao, Linting Xun, Ruochang Li, Ping Wan Scientific Reports.2026;[Epub] CrossRef
Neferine-enhanced Shenling Baizhu Tang potentiates anti-PD-1 therapy in colorectal cancer liver metastasis via CYP2E1–PPARα–mediated lipid reprogramming Xiaochun Zhang, Yang Yang, Meiqi Zhang, Yanyan Xu, Jun Wang, Chunxia Zhang, Jiabo Gu, Jianlei Liu, Xiaorui Ye, Xinyi Zhang, Heiying Jin Phytomedicine.2026; 156: 158236. CrossRef
Decoding the Gut-Liver Crosstalk: Microbial Metabolite- Driven AhR Signalling Networks in MASLD Pathogenesis Ting-yu Song, Xiu-fang Yang, Si-qi Yang, Jin-yong Peng, Li-na Xu International Immunopharmacology.2026; 180: 116722. CrossRef
Hypoxia-inducible factor-1 as targets for neuroprotection : from ferroptosis to Parkinson’s disease Changyong Wang, Shanyu Lv, Hongyan Zhao, Guoguo He, Hongshuo Liang, Kemiao Chen, Minghai Qu, Yonghua He, Chaoyan Ou Neurological Sciences.2025; 46(3): 1111. CrossRef
Untargeted metabolite profiling reveals metabolic disorders in livers of rats with mepiquat exposure Chuanqin Hu, Xinyu Song, Jing Wang, Baoguo Sun Journal of Food Science.2025;[Epub] CrossRef
Integrated transcriptomics and metabolomics to explore the varied hepatic toxicity induced by aged- and pristine-microplastics: in vivo and human-originated liver organoids-based in vitro study Wei Cheng, Yifei You, Hange Chen, Yue Zhou, Yan Feng, Yan Wang Environmental Research.2025; 280: 121820. CrossRef
Binge drinking triggers VGLUT3-mediated glutamate secretion and subsequent hepatic inflammation by activating mGluR5/NOX2 in Kupffer cells Keungmo Yang, Kyurae Kim, Tom Ryu, Young-Ri Shim, Hee-Hoon Kim, Sung Eun Choi, Min Jeong Kim, Katherine Po Sin Chung, Eunmi Lee, Kwang Woo Lee, Jehwi Jeon, Pilhan Kim, Young Seo Kim, Taeyun Ku, Haengdueng Jeong, Ki Taek Nam, Gyumin Lim, Dong Wook Choi, Se Nature Communications.2025;[Epub] CrossRef
Vitamin K Nutritional Status and Disease Risk - A Mendelian Randomization Analysis Yundan Qu, Si Zhao, Xinhe Cai, Hanxue Huang, Pan Xie, Jingbo Peng, Wei Zhang, Honghao Zhou, Xi Li, Yi Chen, Yu Zhang Journal of Dietary Supplements.2025; 22(5): 775. CrossRef
Pharmacodynamic effects and mechanism of Pueraria lobata-Schisandra chinensis combination in the treatment of alcoholic liver disease Shihao Zhang, Ding Liu, Dongyan Guo, Chongbo Zhao, Yajun Shi, Junbo Zou, Huanxian Shi, Jiangxue Cheng, Jing Sun, Xiaofei Zhang Fitoterapia.2025; 187: 106873. CrossRef
Psyllium fiber improves hangovers and inflammatory liver injury by inhibiting intestinal drinking Keungmo Yang, Tom Ryu, Beom Sun Chung Frontiers in Pharmacology.2024;[Epub] CrossRef
Drug-Related Pyroglutamic Acidosis: Systematic Literature Review Tessa Scafetta, Orsolya Kovacs, Gregorio P. Milani, Gabriel Bronz, Sebastiano A. G. Lava, Céline Betti, Federica Vanoni, Mario G. Bianchetti, Pietro B. Faré, Pietro Camozzi Journal of Clinical Medicine.2024; 13(19): 5781. CrossRef
New insights in the pathogenesis of alcohol-related liver disease: The metabolic, immunologic, and neurologic pathways☆ Tom Ryu, Kyurae Kim, Sung Eun Choi, Katherine Po Sin Chung, Won-Il Jeong Liver Research.2023; 7(1): 1. CrossRef
Exosome-Based Delivery of Super-Repressor IκBα Alleviates Alcohol-Associated Liver Injury in Mice Hee-Hoon Kim, Young-Ri Shim, Sung Eun Choi, Tolulope Esther Falana, Jae-Kwang Yoo, So-Hee Ahn, Minhye Park, Hyangmi Seo, Chulhee Choi, Won-Il Jeong Pharmaceutics.2023; 15(2): 636. CrossRef
Anticancer therapeutic effect of ginsenosides through mediating reactive oxygen species Xiaonan Li, Donghui Cao, Siming Sun, Yuehui Wang Frontiers in Pharmacology.2023;[Epub] CrossRef
The Protective Effects of Ganoderic Acids from Ganoderma lucidum Fruiting Body on Alcoholic Liver Injury and Intestinal Microflora Disturbance in Mice with Excessive Alcohol Intake Ying-Jia Cao, Zi-Rui Huang, Shi-Ze You, Wei-Ling Guo, Fang Zhang, Bin Liu, Xu-Cong Lv, Zhan-Xi Lin, Peng-Hu Liu Foods.2022; 11(7): 949. CrossRef
First
Prev
