Nrf2 as a redox checkpoint in autoimmune joint inflammation: microenvironmental redox control across the arthritis spectrum

作者：Mingwang Zhou, Haiyuan Gao, Xiaoping Wang, Zhenhua Shi, Xing Yang, YuNan Li, Xiaodong Li, Yongqiang Zhao · 发表于：Frontiers in Immunology · 年份：2026 · DOI：10.3389/fimmu.2026.1775908 · 被引用次数：2 · 研究领域：Spondyloarthritis Studies and Treatments、Genomics, phytochemicals, and oxidative stress、Inflammasome and immune disorders

Arthritis comprises a spectrum of immune-mediated joint disorders, with rheumatoid arthritis (RA) representing prototypic autoimmunity and psoriatic arthritis (PsA) and ankylosing spondylitis (AS) spanning an autoinflammation-autoimmunity continuum. Across this spectrum, oxidative stress and inflammatory signaling reinforce each other within synovial/entheseal niches, sustaining immune activation and progressive structural damage. Excess reactive oxygen species (ROS) injure chondrocytes and synoviocytes, activate NF-κB and the NLRP3 inflammasome, and reprogram stromal-immune interactions; inflammatory mediators further increase ROS via NADPH oxidases, mitochondrial dysfunction, and immunometabolic perturbations, sustaining a "ROS-inflammation-ROS" loop. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a redox-responsive transcription factor that, upon release from Keap1, drives antioxidant response element-dependent cytoprotective programs. Beyond antioxidation, Nrf2 can dampen NF-κB-linked transcription and modulate ferroptosis, pyroptosis, and autophagy while shaping macrophage and fibroblast-like synoviocyte states. Collectively, these actions position Nrf2 as a context-dependent redox checkpoint that may constrain inflammatory amplification and tune autoimmune-relevant processes (e.g., inflammatory antigen presentation and effector persistence) largely via microenvironmental remodeling rather than direct TCR/BCR inhibition. Here, we (i) map Nrf2-dependent versus Nrf2...