{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSLC22A11 encodes the organic anion transporter 4 (OAT4), which has been identified in genome‐wide association studies as a key regulator of serum uric acid homeostasis. Multiple independent studies have found that both common and rare variants in SLC22A11 are associated with changes in urate handling that predispose individuals to hyperuricemia and gout—particularly the renal underexcretion subtype—in diverse populations such as Europeans, Japanese, and Indians."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nOn a molecular and physiological level, SLC22A11 (hOAT4) is predominantly expressed on the apical membrane of renal proximal tubule cells and in the placenta, where it facilitates the transport of a broad range of organic anions. Functional experiments have demonstrated that hOAT4 mediates the high‐affinity uptake and efflux of substrates such as urate, estrone sulfate, dehydroepiandrosterone sulfate, tetracycline, and even certain environmental chemicals like perfluoroalkyl substances. Its activity is tightly regulated by processes including glycosylation—as evidenced by alterations in membrane targeting and substrate binding affinity—as well as by interactions with PDZ proteins, caveolin-1, and ubiquitin ligases. In addition, multiple signaling pathways involving activators such as PKC, insulin-like growth factor 1 (IGF-1), and serum- and glucocorticoid-inducible kinase 2 (sgk2) modulate hOAT4 expression and trafficking, ensuring proper renal secretion/reabsorption and placental hormone precursor uptake for estriol biosynthesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its established roles in urate and drug handling, variation in SLC22A11 is emerging as a contributor to broader metabolic traits. Recent genetic studies have linked SLC22A11 variants to differences in body mass index and obesity phenotypes, suggesting that modulation of OAT4 function may influence systemic metabolic regulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Melanie Kolz, Toby Johnson, Serena Sanna, et al. 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