Hyperuricemia in 2025: Epidemiology, Mechanisms, Associated Conditions and Treat-to-target Management

Hyperuricemia has moved from a niche biochemical finding to a clinically relevant cardio-renal-metabolic risk state. This review synthesises contemporary evidence on uric acid biology, epidemiology, and management. We outline sources and biochemistry of urate, the hepatic xanthine oxidoreductase pathway, and the coordinated roles of renal and intestinal transporters that set steady-state serum levels, emphasising URAT1, GLUT9, NPT1, NPT4, and ABCG2, as well as the organic anion transporters OAT1 and OAT3, which import uric acid from the blood into proximal tubule cells. We summarise definitions, diagnostic thresholds, and global prevalence with sex-specific ranges, then differentiate asymptomatic hyperuricemia from crystal disease. Clinical sections integrate mechanistic links between soluble and crystalline urate and organ injury: inflammasome-mediated gout; tubulointerstitial injury, arteriolopathy, and obstructive pathways in kidney disease; oxidative stress, endothelial dysfunction, and vascular remodelling in hypertension, atherosclerosis, and coronary events; and metabolic pathways involving fructose metabolism, insulin resistance, and hepatic lipogenesis that connect hyperuricemia to metabolic syndrome and MAFLD. We appraise clinical evidence across cohorts, imaging, genetics, and randomised trials, distinguishing strong causal domains such as gout and uric acid nephrolithiasis from associative domains where treatment decisions should be individualised. A practical, phenotype-driven treat-to-target framework is presented that prioritises xanthine oxidase inhibition, adds uricosuric therapy for underexcretion, embeds lifestyle therapy, and applies safety strategies including HLA-B*58:01 screening in high-risk ancestries. We conclude with research gaps and priorities, including transporter-targeted strategies, intestinal urate quantification, pragmatic trials in enriched phenotypes, and clarity on long-term cardiovascular and renal outcomes.