Dual Roles of Free Fatty Acids in Gout Pathogenesis: Inflammatory Drivers and Metabolic Mediators

Gout, a prototypical crystal-induced arthropathy, is characterized by a complex interaction between metabolic dysregulation and inflammatory activation. Although monosodium urate (MSU) crystal deposition remains the central pathognomonic feature, accumulating evidence suggests that free fatty acids (FFAs) play a significant role as co-modulators in the disease's pathogenesis. This review systematically examines the dual role of FFAs in gout pathophysiology: (1) their pro-inflammatory effects during gout flares through direct modulation of innate immune responses, and (2) their role as metabolic modulators contributing to disease comorbidities. We explore the molecular mechanisms by which saturated and n-6 polyunsaturated fatty acids (PUFAs) promote NLRP3 inflammasome activation, ultimately leading to cytokine storm formation and acute inflammatory responses. Paradoxically, short-chain fatty acids and n-3 polyunsaturated fatty acids exhibit anti-inflammatory properties and confer protection against gout flares via distinct immunomodulatory pathways. The review further examines FFA-mediated metabolic disturbances associated with gout, such as insulin resistance, renal fibrosis, and non-alcoholic fatty liver disease. Additionally, this review provides novel insights into targeted therapeutic strategies for the adjuvant treatment of gout, including lipid-targeted therapy, microbiome modulation, and dietary recommendations regarding polyunsaturated fatty acids.