Owing to renal reabsorption and the loss of uricase activity, uric acid (UA) is strictly maintained at a higher physiological level in humans than in other mammals, which provides a survival advantage during evolution but increases susceptibility to certain diseases such as gout. Although monosodium urate (MSU) crystal precipitation has been detected in different tissues of patients as a trigger for disease, the pathological role of soluble UA remains controversial due to the lack of causality in the clinical setting. Abnormal elevation or reduction of UA levels has been linked to some of pathological status, also known as U-shaped association, implying that the physiological levels of UA regulated by multiple enzymes and transporters are crucial for the maintenance of health. In addition, the protective potential of UA has also been proposed in aging and some diseases. Therefore, the role of UA as a double-edged sword in humans is determined by its physiological or non-physiological levels. In this review, we summarize biosynthesis, membrane transport, and physiological functions of UA. Then, we discuss the pathological involvement of hyperuricemia and hypouricemia as well as the underlying mechanisms by which UA at abnormal levels regulates the onset and progression of diseases. Finally, pharmacological strategies for urate-lowering therapy (ULT) are introduced, and current challenges in UA study and future perspectives are also described.

中文翻译：

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尿酸与健康和疾病：从生理功能到致病机制

由于肾脏重吸收和尿酸酶活性丧失，人类的尿酸（UA）严格维持在比其他哺乳动物更高的生理水平，这在进化过程中提供了生存优势，但增加了对某些疾病（如痛风）的易感性。尽管已在患者的不同组织中检测到尿酸钠（MSU）晶体沉淀作为疾病的触发因素，但由于临床环境中缺乏因果关系，可溶性尿酸的病理作用仍然存在争议。UA水平的异常升高或降低与某些病理状态有关，也称为U形关联，这意味着受多种酶和转运蛋白调节的UA生理水平对于维持健康至关重要。此外，UA 在衰老和某些疾病中也具有保护潜力。因此，UA对人类的双刃剑作用是由其生理或非生理水平决定的。在这篇综述中，我们总结了UA的生物合成、膜运输和生理功能。然后，我们讨论高尿酸血症和低尿酸血症的病理参与以及异常水平的UA调节疾病发生和进展的潜在机制。最后，介绍了降尿酸治疗（ULT）的药理学策略，并描述了 UA 研究当前的挑战和未来的前景。