2. Academic Validation
  3. Downregulation of FcRn promotes ferroptosis in herpes simplex virus-1-induced lung injury

Downregulation of FcRn promotes ferroptosis in herpes simplex virus-1-induced lung injury

  • Cell Mol Life Sci. 2025 Jan 6;82(1):36. doi: 10.1007/s00018-024-05555-y.
Shaoju Qian 1 2 3,  Danqiong Zhang 1,  Ruixue Li 4,  Xiaoming Sha 1,  Shuao Lu 1,  Lin Pan 1,  Xianfeng Hui 1 2 3,  Tiesuo Zhao 1 2 3,  Xiangfeng Song 1 2 3,  Lili Yu 5 6 7
Affiliations

Affiliations

  • 1 School of Basic Medical Sciences, Xinxiang Medical University, #601 Jinsui Road, Xinxiang, 453003, Henan, China.
  • 2 Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, 453003, China.
  • 3 Xinxiang Engineering Technology Research Center of Immune Checkpoint Drug for Liver-Intestinal Tumors, Henan, 453003, China.
  • 4 Department of Otolaryngology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453003, China.
  • 5 School of Basic Medical Sciences, Xinxiang Medical University, #601 Jinsui Road, Xinxiang, 453003, Henan, China. merrys222@126.com.
  • 6 Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, 453003, China. merrys222@126.com.
  • 7 Xinxiang Engineering Technology Research Center of Immune Checkpoint Drug for Liver-Intestinal Tumors, Henan, 453003, China. merrys222@126.com.
PMID: 39760769 DOI: 10.1007/s00018-024-05555-y
Abstract

Herpes simplex virus type I (HSV-1) Infection is associated with lung injury; however, no specific treatment is currently available. In this study, we found a significant negative correlation between FcRn levels and the severity of HSV-1-induced lung injury. HSV-1 Infection increases the methylation of the FcRn promoter, which suppresses FcRn expression by upregulating DNMT3b expression. Analysis of the FcRn promoter revealed that the -1296- to -919-bp region is the key regulatory region, with the CG site at -967/-966 bp being the critical methylation site. The transcription factor JUN binds to this CG site to increase FcRn transcription; however, its activity was significantly inhibited by DNMT3b overexpression. Moreover, 5-Aza-2 effectively reduced HSV-1-induced lung injury and inhibited Ferroptosis. Transcriptomic Sequencing revealed that the Ferroptosis pathway was highly activated in the lung tissues of FcRn-knockout mice via the p53/SLC7A11 pathway. Furthermore, in vivo and in vivo experiments showed that FcRn knockout aggravated lung epithelial cell inflammation by promoting ferroptosis; however, this effect was reversed by a Ferroptosis inhibitor. Thus, HSV-1 Infection suppressed FcRn expression through promoter methylation and promoted Ferroptosis and lung injury. These findings reveal a novel molecular mechanism underlying viral lung injury and suggest potential therapeutic strategies for targeting FcRn.

Keywords

DNMT3b; FcRn; Ferroptosis; HSV-1; Lung injury.

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