Uric Acid as a Redox Switch in Gout: Linking Xanthine Oxidoreductase-Derived ROS, NLRP3 Inflammasome Activation and Emerging Ferroptotic Mechanisms

Abstract

Gout is a crystal-induced inflammatory arthritis driven by hyperuricemia and monosodium urate (MSU) crystal deposition, yet urate burden alone does not explain why only a subset of hyperuricemic individuals develops clinical disease, why acute flares are usually self-limited, or why gout clusters with renal and cardiometabolic comorbidity. This structured narrative review uses a gout-specific redox-switch framework, defined as a context-dependent shift in uric acid biology according to concentration, compartment, crystallization state, xanthine oxidoreductase (XOR) activity, inflammatory priming, and disease stage rather than as a binary molecular event. We integrate evidence on XOR-derived reactive oxygen species (ROS), mitochondrial stress, NLRP3 inflammasome signaling, neutrophil oxidative responses, neutrophil extracellular traps (NETs), lipid peroxidation, and potential ferroptosis-related mechanisms. Evidence is classified into five categories: established, mechanistically supported, human-associative, conceptual, and emerging/unvalidated. The available human data support lipid-peroxidation and ferroptosis-associated molecular signatures, but do not yet establish ferroptotic cell death as a driver of gout. Therapeutic implications are therefore framed conservatively: urate-lowering therapy remains foundational, whereas redox-directed approaches require pathway specificity, disease-stage definition, and biomarker validation. The redox-switch concept is proposed as an organizing framework for mechanistic and translational research, not as a validated clinical algorithm.