2. Academic Validation
  3. Deficiency of NRF2 aggravates BLM-induced systemic sclerosis-associated fibrosis and inflammation in mice

Deficiency of NRF2 aggravates BLM-induced systemic sclerosis-associated fibrosis and inflammation in mice

  • Int Immunopharmacol. 2026 Feb 15:171:116130. doi: 10.1016/j.intimp.2025.116130.
Qianyu Zhu 1,  Pan Guo 2,  Ruotong Wang 3,  Jingyu Zhang 1,  Hong Chen 1,  Junkai Huang 1,  Jing Luo 1,  Xiaoxia Li 4,  Lizhi Hu 5
Affiliations

Affiliations

  • 1 Immunology Department, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Medical University, Tianjin 300070, China.
  • 2 Tianjin Pediatric Research Institute, Tianjin Key Laboratory of Birth Defects for Prevention and Treatment, Tianjin Children's Hospital (Children's Hospital of Tianjin University), Tianjin 300134, China. Electronic address: [email protected].
  • 3 College of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
  • 4 College of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China. Electronic address: [email protected].
  • 5 Immunology Department, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Medical University, Tianjin 300070, China; Department of Ophthalmology, Second Hospital of Tianjin Medical University, Tianjin 300211, China. Electronic address: [email protected].
PMID: 41485256 DOI: 10.1016/j.intimp.2025.116130
Abstract

Background: Systemic sclerosis (SSc), also called scleroderma, is a chronic autoimmune connective tissue disorder characterized by fibrosis of the skin and internal organs and vasculopathy. Its pathogenesis involves abnormal activation of fibroblasts, inflammatory response and oxidative stress. Studies have shown that nuclear factor E2-related factor 2 (NRF2), as a key transcription factor regulating oxidative stress, not only affects the process of organ fibrosis, but also dynamically modulates the inflammatory response. Data from clinical studies showed that the remarkably abnormal expression of NRF2 at skin lesions in SSc patients suggested the pathological relevance between NRF2 and SSc.

Methods: Wild type (WT) mice and NRF2 Knockout (NRF2 KO) mice were subcutaneously injected with Bleomycin (BLM) as an SSc mouse model, and primary mouse fibroblasts were induced through BLM and H2O2 as vitro model to investigate the role of NRF2 in the onset and progression of SSc.

Results: NRF2 deficiency exacerbated the BLM-induced skin hyperplasia and Collagen deposition in mice, compared with the WT group. In addition, NRF2 deficiency significantly regulated the expression of the genes associated with skin fibrosis, inflammatory response and oxidative stress.

Conclusion: NRF2 deficiency promotes fibrosis, inflammation and oxidative stress in SSc-like mice by activating JAK/STAT signaling pathway. Our research provides a new potential target and its underlying mechanisms for the clinical treatment of scleroderma.

Keywords

Inflammatory response; NRF2; Oxidative stress; Systemic sclerosis.

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