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Background: Interferon regulatory factor 4 (IRF4) is a crucial member of the IRF family of transcription factors and is pivotal in orchestrating the body's defense against tumors and infections by modulating the differentiation and functionality of immune cells. The role of IRF4 in mice during Schistosoma japonicum infection, as well as the effects of IRF4 deficiency on myeloid-derived suppressor cells (MDSCs), remains inadequately understood., Methods: Hematoxylin and eosin staining was used to evaluate the pathological damage in different organs of mice following infection with S. japonicum. Flow cytometry was employed to study the effect of IRF4 on the proliferation and function of myeloid-derived suppressor cells (MDSCs) in S. japonicum-infected mice., Results: Knockout of IRF4 in myeloid cells significantly mitigated pathological damage to the liver and lungs in mice infected with S. japonicum. Knockout of IRF4 in myeloid cells also inhibited the expansion and functionality of MDSCs by downregulating programmed death ligand 2 (PD-L2) expression and interleukin-1 alpha (IL-1α) secretion in mice infected with S. japonicum. Mechanistic studies revealed that IRF4 deficiency inhibited the expansion and function of MDSCs and that this inhibition was mediated by the STAT3 and AKT signaling pathways. Also, IRF4 myeloid knockout promoted the expansion of T cells in S. japonicum-infected mice, but had no significant effect on B cell aggregation., Conclusions: Overall, these findings highlight the importance of IRF4 in regulating MDSCs and their impact on tissue damage during S. japonicum infection, providing valuable insights into potential therapeutic targets for managing the pathological consequences of this parasitic infection., Competing Interests: Declarations. Ethics approval and consent to participate: All animal experiments in this study are in accordance with the Chinese National Institute of Health Guide for the Care and Use of Laboratory Animals and have been approved by the Laboratory Animal Use and Care Committee of Guangzhou Medical University. The license number of strict enforcement is S2022-246. Consent for publication: All authors unanimously consent to the submission of the manuscript for publication. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)