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  3. RSAD2: A pathogenic interferon-stimulated gene at the maternal-fetal interface of patients with systemic lupus erythematosus

RSAD2: A pathogenic interferon-stimulated gene at the maternal-fetal interface of patients with systemic lupus erythematosus

  • Cell Rep Med. 2025 Mar 18;6(3):101974. doi: 10.1016/j.xcrm.2025.101974.
Xiaoyu Ding 1,  Yonggang Zhou 2,  Xiaofeng Qiu 1,  Xiuxiu Xu 1,  Xinyu Hu 1,  Jingkun Qin 1,  Yulan Chen 3,  Min Zhang 4,  Jieqi Ke 5,  Zhenbang Liu 6,  Ying Zhou 5,  Chen Ding 7,  Nan Shen 8,  Zhigang Tian 1,  Binqing Fu 9,  Haiming Wei 10
Affiliations

Affiliations

  • 1 The National Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China; Institute of Immunology, University of Science and Technology of China, Hefei, China.
  • 2 The National Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China; Institute of Immunology, University of Science and Technology of China, Hefei, China; Department of Obstetrics and Gynecology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China. Electronic address: ygzhou@ustc.edu.cn.
  • 3 Department of Rheumatology and Immunology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, China.
  • 4 Department of Rheumatology and Immunology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
  • 5 Department of Obstetrics and Gynecology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China.
  • 6 The National Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China.
  • 7 Institute of Biomedical Sciences, State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200433, China.
  • 8 Shanghai Institute of Rheumatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China.
  • 9 The National Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China; Institute of Immunology, University of Science and Technology of China, Hefei, China; Department of Obstetrics and Gynecology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China. Electronic address: fbq@ustc.edu.cn.
  • 10 The National Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China; Institute of Immunology, University of Science and Technology of China, Hefei, China. Electronic address: ustcwhm@ustc.edu.cn.
PMID: 39983716 DOI: 10.1016/j.xcrm.2025.101974
Abstract

Pregnancy disorders in patients with autoimmune diseases or viral infections are often associated with an excessive response of type I interferons. We identify radical S-adenosyl methionine domain containing 2 (RSAD2) as a pathogenic interferon-stimulated gene (ISG) associated with pregnancy complications in systemic lupus erythematosus (SLE). The increased expression of RSAD2 mainly occurs in macrophages and structural cell populations at the maternal-fetal interface of pregnant patients with SLE. The elevation of RSAD2 leads to the accumulation of diacylglycerol lipids in the placenta, impairing the necessary vascular development for the fetus. Depletion of Rsad2 in pregnant mice models exposed to type I interferon inducers significantly reduces lipid accumulation, vascular injury, and embryo development disorders. An RSAD2 inhibitor, L-chicoric acid (LCA), alleviates lipid accumulation and vascular damage, improving pregnancy outcomes in SLE-induced and spontaneous mouse models. This study proposes the potential of targeting RSAD2 to improve pregnancy outcomes in individuals with heightened type I interferon response.

Keywords

RSAD2; abnormal pregnancy outcomes; pathogenic interferon-stimulated genes; systemic lupus erythematosus; the maternal-fetal interface.

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