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

## TL;DR

This paper explores how the Nrf2 protein helps control inflammation in different types of arthritis by managing oxidative stress and immune responses.

## Contribution

The study identifies Nrf2 as a redox checkpoint that modulates immune processes in autoimmune joint inflammation.

## Key findings

- Nrf2 regulates antioxidant and anti-inflammatory pathways in synovial and entheseal niches.
- Nrf2 influences immune cell states and processes like pyroptosis and autophagy in arthritis.
- Nrf2-centered therapies may offer new treatment strategies for autoimmune arthritides.

## Abstract

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.