The evolutionary loss of hepatic uricase activity completely blocks uric acid (UA) degradation in purine metabolism, leading to a higher physiological level in humans and certain primates than in other mammals, which may provide a series of physiological advantages (Ames, Cathcart, Schwiers, & Hochstein, 1981; Christen, Peacock, Christen, & Wacker, 1970; Oda, Satta, Takenaka, & Takahata, 2002; Wu, Muzny, Lee, & Caskey, 1992). UA is one of the most abundant antioxidants in humans (Glantzounis, Tsimoyiannis, Kappas, & Galaris, 2005) and is crucial for the maintenance of blood pressure (Watanabe et al., 2002). On the basis of antioxidant property, UA has also been proposed to exhibit neuroprotective effects (Kutzing & Firestein, 2008; Lu et al., 2016; Scott et al., 2002) and to provide a physiological defense against aging and cancers (Ames et al., 1981). Although the molecular basis of UA physiology remains largely unknown, UA levels within a normal range control its physiological functions that are essential for the maintenance of health.

Indeed, abnormal changes in UA levels, such as hypouricemia and hyperuricemia, have been associated with the risk of various diseases (Crawley, Jungels, Stenmark, & Fini, 2022; Kutzing & Firestein, 2008). For instance, hyperuricemia promotes the precipitation of monosodium urate (MSU) crystals to activate the NLRP3 inflammasome (Martinon, Pétrilli, Mayor, Tardivel, & Tschopp, 2006), resulting in the well-known pathological process of gout (Dalbeth, Gosling, Gaffo, & Abhishek, 2021). Unlike MSU crystals, the pathological role of soluble UA has been investigated and debated for a long time. Despite the lack of causality in the clinical setting, some experimental studies argued that UA at high levels, independent of MSU crystals, directly regulates the onset and progression of other diseases such as kidney diseases, cardiovascular diseases (CVD), and liver diseases. In addition, abnormal reduction of UA levels, especially hypouricemia, may weaken the physiological defense, including but not limited to antioxidant property, thereby contributing to certain diseases. Nevertheless, it remains an open question regarding that UA at abnormal levels is a trigger and/or a hallmark in diseases.

Therefore, this review explores the biosynthesis, membrane transport, and physiological functions of UA as well as how UA at abnormal levels regulates certain diseases, including our recent findings, with a brief introduction for urate-lowering medications. All these advances can be integrated into an increasingly detailed understanding of the physiological and pathological roles of UA, thereby promoting the development of therapeutic strategies for UA-related diseases.