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

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-independent nodes in the oxidative stress-inflammation circuit; (ii) compare cell type- and subtype-specific Nrf2 functions across RA, PsA, and AS; (iii) summarize pharmacologic and natural-product Nrf2 activators together with joint-targeted delivery strategies; and (iv) discuss evidence and gaps for Nrf2 in core autoimmune mechanisms, including self-tolerance, antigen handling, and pathogenic immune memory. This synthesis highlights Nrf2 as a mechanistic bridge between redox balance and immune regulation, informing Nrf2-centered therapies for autoimmune and immune-mediated arthritides.