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  3. Novel therapeutic approach for psoriasis: Upregulating FcRn to inhibit ferroptosis and alleviate lesional skin

Novel therapeutic approach for psoriasis: Upregulating FcRn to inhibit ferroptosis and alleviate lesional skin

  • Free Radic Biol Med. 2024 Sep 11:224:797-808. doi: 10.1016/j.freeradbiomed.2024.09.010.
Shaoju Qian 1,  Zishan Yang 1,  Xingyi Zhang 2,  Ruixue Li 3,  Yujie Sun 4,  Zihan Zhang 2,  Yeqing He 2,  Yihang Song 2,  Zhou Tang 2,  Junrui Ding 4,  Shuao Lu 2,  Lili Yu 1,  Xiangfeng Song 1,  Zhinan Yin 5,  Zhongwei Tian 6
Affiliations

Affiliations

  • 1 School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, 453003, China; Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, 453003, China; Xinxiang Engineering Technology Research Center of Immune Checkpoint Drug for Liver-Intestinal Tumors, Henan, 453003, China.
  • 2 School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, 453003, China.
  • 3 Department of Otolaryngology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453003, China.
  • 4 Department of Dermatology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453000, China.
  • 5 The Biomedical Translational Research Institute, School of Medicine, Jinan University, Guangzhou, 510632, China. Electronic address: tzhinan@jnu.edu.cn.
  • 6 Department of Dermatology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453000, China. Electronic address: zhonwt@xxmu.edu.cn.
PMID: 39270944 DOI: 10.1016/j.freeradbiomed.2024.09.010
Abstract

Psoriasis, a chronic inflammatory skin disease, is characterized by complex immune dysregulation and oxidative stress responses. The neonatal Fc receptor (FcRn) plays a crucial role in the development of autoimmune diseases. Analysis of clinical psoriasis samples demonstrated a negative correlation between FcRn expression in skin lesions and disease severity. However, the role of FcRn in this process remains unclear. This study aimed to investigate the involvement of FcRn in the pathogenesis and progression of psoriasis. In an imiquimod (IMQ)-induced psoriasis-like mouse model, FcRn expression was significantly decreased in the lesional skin, and transcriptome Sequencing of the skin revealed activation of the Ferroptosis pathway in psoriasis. This led to the hypothesis that FcRn could potentially regulate Ferroptosis via the signal transducer and activating transcription factor 3 (STAT3)/solute carrier family 7 member 11 (SLC7A11) axis. Further experiments showed exacerbated psoriasis-like lesional skin and Ferroptosis in FcRn-knockout mice, whereas intervention with the Ferroptosis inhibitor Fer-1 or STAT3 Inhibitor Stattic alleviated these symptoms. Critical binding sites for the transcription factor STAT3 were identified in the SLC7A11 promoter region at positions -1185 and -564 using the luciferase reporter assays and chromatin immunoprecipitation. The administration of 1,4-naphthoquinone (NQ), an FcRn agonist, effectively alleviated psoriasis-like skin lesions by inhibiting Ferroptosis. This study highlights the molecular mechanisms of action of FcRn in psoriasis and provides an experimental basis for the development of novel therapeutic strategies targeting FcRn.

Keywords

Ferroptosis; Neonatal Fc receptor; Psoriasis; STAT3/SLC7A11 axis.

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