Evolutionary, genetic, and mechanistic insights into uric acid regulation and sex differences

Hyperuricemia is a metabolic disorder characterized by abnormally elevated blood uric acid levels.Elevated serum uric acid levels can lead to crystal deposition in joints and tissues, causing inflammation and pain characteristic of gout and also contributing to renal dysfunction and vascular complications.It is closely associated with various health issues including gout, kidney stones, chronic kidney disease, and cardiovascular diseases.Understanding the underlying causes of hyperuricemia is critical.This review focuses on the causes of hyperuricemia from several key perspectives: the changes in uricase during evolution and the occurrence of pseudogenic mutations; the impact of uric acid transporters such as SLC22A12, SLC2A9, and ABCG2 on uric acid levels; and summarizes sex-related differences in clinical manifestations and differentially expressed genes.Additionally, it explores the potential mechanisms of uric acid regulation from hormonal, transcription factor, and epigenetic perspectives, integrating the findings from previous studies.By integrating insights from evolutionary biology, genetics, epidemiology, and molecular biology, this review aims to offer a comprehensive framework for understanding hyperuricemia.This highlights the need for new approaches in both research and clinical practice to advance our knowledge of hyperuricemia and improve patient outcomes through innovative diagnostic tools or tailored therapies.