@article{Jiang2025, 
author = {Yao Jiang and Peida Yang and Bo Yao and Liang Zhang and Man Yang and Yiyi Chen and Lunzhi Yuan and Junyu Chen and Jinhang He and Xing Lei and Feng Chen and Mingxi Yue and Siping Yan and Tong Cheng and Yixin Chen and Quan Yuan and Jun Zhang and Shuhai Lin and Tianying Zhang and Ningshao Xia},
title = {Prophylactic and therapeutic itaconate treatment alleviates COVID-19-associated lung injury},
year = {2025},
journal = {hLife},
volume = {3},
number = {11},
pages = {551-564},
keywords = {itaconate (ITA), coronavirus disease 2019 (COVID-19), acute lung injury (ALI), macrophage, multiomics},
url = {https://www.sciopen.com/article/10.1016/j.hlife.2025.06.006},
doi = {10.1016/j.hlife.2025.06.006},
abstract = {Itaconate (ITA), an immunomodulatory metabolite with known anti-inflammatory properties, has underexplored therapeutic or prophylactic potential against coronavirus disease 2019 (COVID-19). Using an interanimal transmission golden hamster model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced acute lung injury, we first assessed ITA changes in dNS1-RBD-vaccinated hamsters via metabolomic profiling. Then, we evaluated prophylactic intranasal (20 mg/kg at 9, 6, and 3 days before SARS-CoV-2 infection) and therapeutic intraperitoneal (100 mg/kg at 6, 24, and 48 hours post-infection) ITA administration, assessed by histopathology, transcriptomic, and metabolomic profiling, followed by multi-omics integration, including gene expression clustering, pathway enrichment, and cytokine/chemokine–metabolites correlation analyses. Public bronchoalveolar lavage fluid (BALF) single-cell RNA-sequencing (scRNA-seq) datasets from COVID-19 patients were re-analyzed to explore macrophage heterogeneity. Intranasal dNS1-RBD vaccine upregulated ITA levels, prompting further exploration of its immunomodulatory role. Both prophylactic and therapeutic ITA treatments significantly mitigated weight loss and improved lung pathology. Correlation analyses implied a potential regulatory crosstalk between fatty acid β-oxidation (FAO) and reduced inflammatory response. Re-analysis of BALF scRNA-seq dataset highlighted transcriptional networks involving PPARG, RARA, BHLHE41, TCF7L2, and ESRRA—genes linked to macrophage self-renewal and metabolic homeostasis, which appeared to be preserved in ITA-treated hamsters. These findings underscore ITA’s role in modulating immunometabolic responses, particularly through FAO-driven macrophage reprogramming, to attenuate SARS-CoV-2-induced lung damage. Together, this study provides insights into host-directed therapies targeting metabolic reprogramming to mitigate COVID-19 severity.}
}