Urolithin C Ameliorates Hyperuricemia by Mitigating Renal Dysfunction through ROS-p38/ERK MAPK Axis Suppression

Hyperuricemia (HUA) is a prevalent metabolic disorder, with limited therapeutic options. This study investigated the effects and mechanisms of urolithin C (UroC), a gut-microbiota-derived bioactive metabolite from ellagitannin-rich foods, in the management of HUA. In HUA mice, UroC significantly reduced serum uric acid (SUA) levels, outperforming its analogs, UroA and UroB. UFLC-MS/MS identified free UroC as the primary active form in vivo. Mechanistically, UroC alleviated HUA by enhancing renal UA excretion, while concurrently ameliorating renal oxidative stress and fibrosis. Moreover, UroC inhibited UA-induced p38/ERK MAPK activation by reducing the level of reactive oxygen species (ROS) production. Rescue experiments further confirmed that UroC improved the expression of renal UA transporters and fibrosis markers via p38/ERK MAPK inhibition. These findings highlight UroC as a promising food-derived candidate for HUA management, promoting renal protection and enhancing UA excretion via the ROS-p38/ERK MAPK axis.