Uric acid (UA) is the end product of purine metabolism in humans. Liver, which contains multiple enzymes involved in purine metabolism, is the primary site of purine breakdown and thus the main source of UA production. The kidneys and intestines are the key organs responsible for UA excretion. Approximately two-thirds of UA is excreted via the kidneys, whereas the remaining one-third is eliminated through extrarenal routes, primarily the intestines. Hyperuricemia (HUA) is a metabolic disorder characterized by elevated serum UA concentrations. It typically results from either overproduction of UA in the liver or underexcretion by the kidneys and intestines. The global prevalence of HUA is increasing annually, now exceeding 14% in many countries. Clinically, HUA is known to trigger gout and urolithiasis and contributes to the development and progression of cardiovascular diseases, chronic kidney disease and metabolic syndrome.

The group of Zhenghong Zuo & Chengyong He published a research paper titled "The guanine nucleotide exchange factor Rin-like is a repressor for renal uric acid excretion in human and mouse" in Science Translational Medicine at Sep 23, 2026. This study identifies RINL (Ras and Rab interactor-like) for the first time as a negative regulator of renal uric acid excretion. Its overexpression or gain-of-function mutation (human P139S/mouse P140S) promotes the endocytosis and lysosomal degradation of the uric acid transporter ABCG2 by activating RAB5C, thereby inhibiting uric acid excretion. The study also found that tetrahydrocurcumin can directly bind to RINL and promote its proteasomal degradation, significantly reducing serum uric acid and improving renal function in multiple hyperuricemia mouse models (a xanthine oxidase inhibitor-induced model, a Uox gene conditional inducible knockout model mimicking human uricase mutations, and hyperuricemia models secondary to severe malaria and chronic kidney disease), providing a novel candidate molecule for the treatment of hyperuricemia.

This study identified RINL (c.415C>T, P139S) as a novel pathogenic mutation through whole-exome sequencing of a family with hyperuricemia. Functional studies showed that the P139S mutation enhances RINL protein stability (escaping proteasomal degradation), and overexpression of this mutant in renal tubular epithelial cells significantly reduces extracellular uric acid and increases intracellular uric acid. A mouse model with the homologous point mutation in mRINL (P140S) knock-in also exhibited elevated serum uric acid, decreased urinary uric acid and FEUA, and renal tubular dilation. In contrast, in RINL-knockout human renal tubular epithelial cells (HK2) and in systemic and renal tubule-specific knockout mice, uric acid excretion was enhanced and serum uric acid was reduced. These findings indicate that RINL is a negative regulator of renal uric acid excretion, and that the functional point mutation or overexpression can induce hyperuricemia.

Mechanistically, RINL, as a guanine nucleotide exchange factor (GEF), directly binds to RAB5C and promotes its GTP-bound (activated) form; activated RAB5C interacts with the uric acid efflux transporter ABCG2, accelerating the internalization of ABCG2 from the apical membrane of renal tubular epithelial cells and its transport to early endosomes and lysosomes for degradation, thereby reducing ABCG2 abundance on the apical membrane of renal tubular epithelial cells and inhibiting uric acid excretion. In RINL-knockout HK2 cells and in systemic and renal tubule-specific knockout mice, ABCG2 protein levels were significantly upregulated. In comparison, RINL expression in the intestine is extremely low, and RINL knockout does not affect intestinal ABCG2 expression or fecal uric acid excretion, indicating that this regulation is kidney tissue-specific and does not affect intestinal uric acid excretion.

Based on molecular docking, cellular experiments, and microscale thermophoresis, the researchers screened more than 1,500 natural products and identified tetrahydrocurcumin, which specifically binds to RINL (with key sites including Leu456, etc.), induces structural destabilization of the RINL protein, and promotes its degradation via the proteasomal pathway. In HK2 cells, tetrahydrocurcumin treatment reduced RINL and restored ABCG2 expression, thereby promoting uric acid secretion in a dose-dependent manner, and this effect was abolished in RINL-knockout cells. In various mouse hyperuricemia models, including those induced by xanthine oxidase inhibitors, liver-specific Uox knockout (mimicking human uricase deficiency), secondary to severe malaria (Plasmodium yoelii 17XL), and chronic kidney disease (induced by folic acid or UUO), oral gavage of tetrahydrocurcumin significantly reduced serum uric acid, creatinine, and blood urea nitrogen, increased urinary uric acid excretion and FEUA, alleviated renal tubular injury, and prolonged the survival of mice with severe malaria. This study confirms the key regulatory role of RINL in uric acid excretion, and inhibiting or targeting RINL for degradation may represent a novel strategy for precision treatment of hyperuricemia.

In summary, this study identified RINL as a novel negative regulator of renal uric acid excretion, and revealed that RINL, as a guanine nucleotide exchange factor, promotes the endocytosis and lysosomal degradation of the uric acid efflux protein ABCG2 by activating RAB5C, thereby inhibiting renal uric acid excretion. Gain-of-function mutations enhance protein stability by escaping proteasomal degradation, aggravating excretion impairment and leading to hyperuricemia. This study also screened and identified tetrahydrocurcumin as a highly efficient RINL degrader, which can specifically bind to RINL and induce its proteasomal degradation, significantly reducing serum uric acid, improving renal function, and prolonging survival in multiple mouse models of hyperuricemia. This study provides a novel target and candidate preventive and therapeutic molecule for the precision treatment of hyperuricemia, opening up a new direction beyond traditional uric acid-lowering drugs (XOD inhibitors and URAT1 inhibitors), and showing promising prospects for clinical translation.

Changshun Han, a doctoral student at the School of Life Sciences, Xiamen University, Professor Chengyong He, and Director Weiping Hu from the Department of Nephrology at the First Affiliated Hospital of Xiamen University are co-first authors of the paper. Professor Zhenghong Zuo from the School of Life Sciences/Xiang'an Hospital Affiliated to Xiamen University and Professor Chengyong He are co-corresponding authors of the paper. The team of Associate Professor Jian Li from the School of Life Sciences, Xiamen University provided malaria parasite-infected mice; Professor Xianming Deng, Professor Bo Wang, and Professor Chensong Zhang and their teams provided guidance and assistance multiple times during the research process; Professor Changgui Li and Professor Wei Wang from Xiang'an Hospital Affiliated to Xiamen University provided important support in clinical samples. Doctoral students Zhiyuan Chen, Xiaoyan Ding, Lingxiao Ye, Sihao Zhu, Zizhen Wang, and Fucong Zhang, master's students Lin Zhong, Shuni Zhuang, Yan Zhang, Yitao Guo, and Yingyi Ren, and undergraduates Tianyun Peng and Zixuan Li from the School of Life Sciences, Xiamen University also made important contributions to this research. This work was supported by the National Natural Science Foundation of China (32571506, 22376174) and the Outstanding Youth Fund of the Natural Science Foundation of Fujian Province (2025J010004).

Link：https://www.science.org/eprint/68ZV8MS8YHR7Z99TTBY3/full?activationRedirect=/doi/full/10.1126/scitranslmed.aed1866.