He Qiongyao, He Wu, Ren Yanlin, Wu Wenbin, Dong Hui, Yuan Gang, Ren Huihui, Wang Xinwei, Lu Fuer, Wang Dingkun
Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Department of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Cell Commun Signal. 2025 May 25;23(1):242. doi: 10.1186/s12964-025-02253-5.
Ferroptosis, an iron-dependent form of programmed cell death, is closely associated with tubular damage in diabetic nephropathy (DN). Glutathione peroxidase 4 (GPX4) is an important anti-oxidant enzyme, and plays a crucial role in protecting against ferroptosis. However, the regulatory mechanism of GPX4 expression levels in renal tubular epithelial cells (RTECs) remains elusive. This study reveals that ferroptosis occurs in the late-stage of DN, and the GPX4 level is significantly downregulated in DN patients, animal models and cell models. By applying database predictions, luciferase reporter assays and chromatin immunoprecipitation, we find that vitamin D receptor (VDR) transcription factor promotes GPX4 expression and plays a key role in inhibiting ferroptosis of RTECs. VDR knockout exacerbates ferroptosis in RTECs and worsens renal function, while intraperitoneal injection of VDR agonist paricalcitol significantly improves renal injury. Proteomics analysis suggests that E3 ligase PRPF19 mediates ubiquitination degradation of VDR and is an important therapeutic target for DN. Therefore, through molecular docking, targeted fishing technology using high-performance affinity beads, and surface plasmon resonance (SPR), we screen and identify berberine (BBR) as a novel inhibitor of PRPF19, which offers renal protection by inhibiting VDR degradation and tubular ferroptosis. These findings elucidate the role of ferroptosis in DN renal tubular injury, and suggest that PRPF19 is a promising therapeutic target.
铁死亡是一种铁依赖性的程序性细胞死亡形式，与糖尿病肾病（DN）中的肾小管损伤密切相关。谷胱甘肽过氧化物酶4（GPX4）是一种重要的抗氧化酶，在抵御铁死亡中起关键作用。然而，肾小管上皮细胞（RTECs）中GPX4表达水平的调控机制仍不清楚。本研究表明，铁死亡发生在DN的晚期，在DN患者、动物模型和细胞模型中，GPX4水平显著下调。通过应用数据库预测、荧光素酶报告基因检测和染色质免疫沉淀，我们发现维生素D受体（VDR）转录因子促进GPX4表达，并在抑制RTECs铁死亡中起关键作用。VDR基因敲除加剧了RTECs中的铁死亡并恶化了肾功能，而腹腔注射VDR激动剂帕立骨化醇可显著改善肾损伤。蛋白质组学分析表明，E3连接酶PRPF19介导VDR的泛素化降解，是DN的一个重要治疗靶点。因此，通过分子对接、使用高性能亲和珠的靶向垂钓技术和表面等离子体共振（SPR），我们筛选并鉴定小檗碱（BBR）为PRPF19的新型抑制剂，其通过抑制VDR降解和肾小管铁死亡提供肾脏保护。这些发现阐明了铁死亡在DN肾小管损伤中的作用，并表明PRPF19是一个有前景的治疗靶点。
