ABCG2 transporter: Structural and functional associations with gout (Review)

ATP‑binding cassette sub‑family G member 2 (ABCG2) is a key regulator of urate homeostasis, and its dysfunction is a major genetic risk factor for hyperuricemia and gout in humans and animals. Initially, ABCG2 was known for its role in multidrug resistance. ABCG2 has since been identified as a high‑capacity urate efflux pump, located at the apical membranes of renal proximal tubules, intestinal enterocytes and hepatic canaliculi. The present review covers the molecular structure, physiological functions and pathophysiological effects of ABCG2, with particular focus on the common Q141K (rs2231142) loss‑of‑function variant. The Q141K variant impairs protein stability and trafficking, reducing urate transport and increasing the risk of gout and cardiorenal comorbidities. The present review explores the central role of ABCG2 within the urate transportome, highlighting its contrasting and cooperative interactions with reabsorptive and secretory transporters, as well as its regulation by novel mechanisms, including the gut microbiome and microbial metabolites. These observations have significant clinical implications for pharmacogenomic approaches, as Q141K variant carriers exhibit a reduced response to uricosuric drugs. The present review also highlights emerging treatments that go beyond standard urate‑lowering therapies, including ABCG2 activators, microbiome modulators and gene‑editing techniques, offering a potential shift toward personalized gout prevention and treatment. Understanding the multifaceted role of ABCG2 is essential for developing targeted strategies to address the root cause of impaired urate excretion.