Cell-type-divergent redox injury in rheumatoid arthritis and systemic lupus erythematosus/lupus nephritis: evidence for ferroptosis-related remodeling and immune amplification

Persistent immune activation alone does not adequately explain the relationship between chronic inflammation, structural damage, and incomplete tissue recovery in rheumatoid arthritis and systemic lupus erythematosus/lupus nephritis. This review uses a cell-type-divergent redox-injury framework to organize how redox imbalance is translated into distinct cellular outcomes. The framework links disruption of SLC7A11–GSH–GPX4 antioxidant defenses to lipid peroxidation, mitochondrial dysfunction, oxidative modification of self-molecules, damage-associated molecular pattern release, and neutrophil extracellular trap–immune complex–type I interferon amplification. Its central premise is that similar inflammatory redox pressure may promote the loss or dysfunction of tissue-supporting or inflammation-resolving cells, permit pathogenic proliferative cells to persist through reinforced anti-ferroptotic defenses, and sustain post-injury immune amplification. Rheumatoid arthritis and systemic lupus erythematosus/lupus nephritis provide the most developed disease-specific evidence and therefore form the primary focus of this review, whereas evidence in other rheumatic diseases remains heterogeneous and is often indirect, transcriptomic, or model-dependent. Even within RA and SLE/LN, however, the maturity of cell-specific mechanistic evidence is uneven: the macrophage HMGB1–TLR4–STAT3 amplification circuit has been demonstrated in a single mechanistic RA study, whereas individual upstream regulators of podocyte ferroptosis-like injury in LN remain incompletely replicated and predominantly supported by preclinical evidence. Within this framework, oxidative stress, ferroptosis, neutrophil extracellular trap formation, and pyroptosis should not be regarded as interchangeable processes. The framework supports a cell-directed therapeutic logic centered on protecting vulnerable structural cells and selected inflammation-resolving immune-cell states, selectively restoring ferroptotic susceptibility in pathogenic proliferative cells, and interrupting downstream inflammatory amplification while avoiding indiscriminate antioxidant or tissue-wide ferroptosis modulation.