Hyperuricemia, characterized by elevated levels of uric acid (urate) in the blood (>6.8 mg/dL), can activate the inflammatory response and lead to gout, hyperuricemic nephropathy, as well as increase the risk of various chronic diseases, including cardiovascular diseases and hypertension [1], [2]. Uric acid, synthesized by xanthine oxidase (XOD) in liver, is the end product of purine metabolism. XOD inhibitors, such as allopurinol and febuxostat, have been employed to manage hyperuricemia by inhibiting uric acid biosynthesis [3], [4]. However, many patients are resistant to XOD inhibitors, rendering them ineffective [5]. Moreover, the utility of XOD inhibitors is limited, as insufficient urate excretion rather than overproduction, accounts for approximately 90 % of patients [6].

The kidney is the primary organ responsible for 70 % of urate elimination [7]. Urate transporter 1 (URAT1), located on the apical side of renal tubular interstitial cells, is responsible for approximately 90 % of urate reabsorption into the bloodstream [8]. To date, URAT1 is the only uricosuric target and has been targeted by numerous uricosuric agents. However, selective URAT1 inhibitors often pose challenges and may lead to significant renal toxicity. For instance, lesinurad [9] was approved as the first selective URAT1 inhibitor, however, it demonstrated severe kidney toxicity, leading to its withdrawal from the market by the FDA in 2019. URAT1 inhibitors inevitably promote regional deposition and increase crystallization of urate in kidney, which can further activate inflammatory responses, leading to renal interstitial fibrosis and nephropathy [10], [11].

Duzallo [12], a combination of XOD and URAT1 inhibitors (lesinurad + allopurinol), demonstrated superior efficacy and response compared to monotherapy. Additionally, clinical trials involving combinations of XOD with URAT1 inhibitors (e.g., benzbrmarone + allopurinol [13], lesinurad + allopurinol [14]) revealed that multistage treatment significantly enhances efficacy and reduces the likelihood of renal injury. XOD/URAT1 dual target inhibitors offer the potential to improve efficacy, reduce drug dosage, and minimize urate deposition in the kidney [15]. This represents a novel trend in hyperuricemia treatment and holds promise for future applications. To date, only two XOD and URAT1 dual inhibitors have entered clinical trials, but the structural information of both remains undisclosed. KUX-1151[16], developed by Kaisheng Pharmaceuticals, demonstrated its ability to induce substantial and rapid reductions in serum uric acid during Phase I studies. RLBN-1001[17], developed by Relburn Metabolomics, has not made progress in its clinical trials. In some patents, several compounds have also been identified as XOD/URAT1 dual inhibitors (Fig. 1). However, how they exert their dual targeting effects is still unclear.

Natural products, as essential resources for lead compounds, often exhibit superior safety compared to chemical drugs [18]. Previously we established an in-house natural product database containing over 800 naturally derived compounds that have been validated for the treatment of gout/hyperuricemia [19]. In this study, we identified digallic acid, an extract from Galla Chinensis herb, through 3D shape-based and docking-based virtual screening methods from our in-house database. Digallic acid showed significant inhibitory effects on both XOD and URAT1. The anion group (carboxyl) contribute significantly to its inhibition activity on both XOD(R880) and URAT1(R477). And its metabolite, gallic acid, was observed to exhibit potent XOD inhibitory activity. Importantly, both compounds demonstrated the characteristic safety profiles and renal protective effects of natural products when compared to chemical drugs. In conclusion, our research indicates that digallic acid and gallic acid are safe and effective anti-hyperuricemic agents that warrant further exploration.