Protocatechualdehyde from Taraxacum officinale Acted as A Competitive Substrate to Inhibit Xanthine Oxidase Attenuates Hyperuricemia

The escalating prevalence of hyperuricemia (HUA) poses a formidable challenge to global public health. As the key rate-limiting enzyme in uric acid (UA) biosynthesis, xanthine oxidase (XOD) remains the primary target for therapeutic intervention. However, the inherent toxicity and adverse effects of existing pharmacotherapies necessitate the exploration of safe, natural alternatives. We identified and isolated protocatechuic aldehyde (PCA) as a highly potent XOD inhibitor (IC₅₀=0.250 mM) from Taraxacum officinale (TO). It significantly outperforming established natural flavonoids. Mechanistically, PCA uniquely functions as a "slow-turnover substrate" via its C1-aldehyde group. This high-affinity binding coupled (Km =14 μM) with a slow catalytic turnover (Kcat=0.014 s−1) created a "kinetic trap". As a result, XOD tied up in PCA processing for a long period and thus continuously blocking xanthine oxidation. Furthermore, PCA was enzymatically oxidized into protocatechuic acid that a safe and bioactive metabolite, which strictly distinguishes it from clinical drugs like allopurinol that generate toxic intermediates. Furthermore, the aldehyde group was a key group for PCA to exert this mechanism. When the aldehyde group was substituted, PCA loses its function as an XOD substrate, and its XOD inhibition activity decreases by 12.35-fold. Subsequent in vivo studies validated the attenuates HUA efficacy of PCA, demonstrating that PCA intervention significantly suppressed XOD activity and reduced UA level in HUA mice. Consequently, PCA restored the disrupted oxidative stress-inflammatory homeostasis and ameliorated HUA-induced renal pathological damage. Overall, our work provided strong scientific evidence supporting TO as a safe and effective dietary supplement or intervention for managing HUA, thereby helping to address the related public health challenges.