Chronic kidney disease (CKD) affects more than 10% of people worldwide and is a leading cause of death. However, the pathogenesis of CKD remains elusive. The oxidative stress and mitochondrial membrane potential were detected using Enzyme-linked immunosorbent assay and JC-1 assay. Co-immunoprecipitation, dual-luciferase assay, chromatin IP, RNA IP and RNA pull-down were used to validate the interactions among genes. Exploiting a H₂O₂-induced fibrosis model in vitro, PUM2 expression was upregulated in Human kidney 2 cell (HK-2) cells, along with reduced cell viability, enhanced oxidative stress, impaired mitochondrial potential, and upregulated expressions of fibrosis-associated proteins. While PUM2 knockdown reversed the H₂O₂-induced injury in HK-2 cells. Mechanically, Wnt/β-catenin pathway activated PUM2 transcription via TCF4. It was further identified that Wnt/β-catenin pathway inhibited YME1L expression through PUM2-mediated destabilizing of its mRNA. PUM2 aggravated H₂O₂-induced oxidative stress, mitochondrial dysfunction, and renal fibrosis in HK-2 cell via suppressing YME1L expression. Our study revealed that Wnt/β-catenin aggravated renal fibrosis by activating PUM2 transcription to repress YME1L-mediated mitochondrial homeostasis, providing novel insights and potential therapeutic targets for the treatment of kidney fibrosis.

慢性肾病 (CKD) 影响着全球 10% 以上的人口，是导致死亡的主要原因。然而，CKD 的发病机制仍不清楚。采用酶联免疫吸附法和JC-1法检测氧化应激和线粒体膜电位。使用免疫共沉淀、双荧光素酶测定、染色质 IP、RNA IP 和 RNA Pull-down 来验证基因之间的相互作用。利用 H ₂ O ₂诱导的体外纤维化模型，人肾 2 细胞 (HK-2) 细胞中 PUM2 表达上调，同时细胞活力降低、氧化应激增强、线粒体电位受损以及纤维化相关蛋白表达上调蛋白质。而PUM2敲除逆转了H ₂ O ₂诱导的HK-2细胞损伤。从机械角度来说，Wnt/β-catenin 通路通过 TCF4 激活 PUM2 转录。进一步发现，Wnt/β-catenin 通路通过 PUM2 介导的 mRNA 不稳定来抑制 YME1L 表达。 PUM2通过抑制YME1L表达，加重H ₂ O ₂诱导的HK-2细胞氧化应激、线粒体功能障碍和肾纤维化。我们的研究表明，Wnt/β-catenin 通过激活 PUM2 转录抑制 YME1L 介导的线粒体稳态来加剧肾纤维化，为肾纤维化的治疗提供了新的见解和潜在的治疗靶点。