雷公藤红素（Cel），源自传统草药雷公藤。 f.，具有抗炎、抗肿瘤和免疫调节活性。据报道，服用细胞相关药物后患者出现肾功能障碍，包括急性肾功能衰竭。然而，Cel引起肾毒性的功能机制尚不清楚。这项研究结合使用基于活性的蛋白质分析和代谢组学分析来区分 Cel 的肾毒性作用的目标。结果表明，Cel 可能直接与参与代谢和线粒体功能的几种关键酶结合。这些酶包括电压依赖性阴离子选择性通道蛋白1（对于维持线粒体构型和功能稳定性至关重要）、丙酮酸羧化酶（参与糖异构化和三羧酸循环）、脂肪酸合酶（与脂肪酸的β-氧化相关）和丙酮酸激酶 M2（与有氧呼吸相关）。蛋白质组学和代谢组学分析证实，细胞靶向蛋白会破坏一些代谢生物合成过程并促进线粒体功能障碍。最终，Cel 加剧了肾细胞凋亡。这些累积结果让我们深入了解细胞引起的肾毒性的潜在机制。它们还可能促进拮抗药物的开发，以减轻 Cel 对肾脏的有害影响并改善其临床应用。© 作者。

Celastrol (Cel), derived from the traditional herb Tripterygium wilfordii Hook. f., has anti-inflammatory, anti-tumor, and immunoregulatory activities. Renal dysfunction, including acute renal failure, has been reported in patients following the administration of Cel-relative medications. However, the functional mechanism of nephrotoxicity caused by Cel is unknown. This study featured combined use of activity-based protein profiling and metabolomics analysis to distinguish the targets of the nephrotoxic effects of Cel. Results suggest that Cel may bind directly to several critical enzymes participating in metabolism and mitochondrial functions. These enzymes include voltage-dependent anion-selective channel protein 1 (essential for maintaining mitochondrial configurational and functional stability), pyruvate carboxylase (involved in sugar isomerization and the tricarboxylic acid cycle), fatty acid synthase (related to β-oxidation of fatty acids), and pyruvate kinase M2 (associated with aerobic respiration). Proteomics and metabolomics analysis confirmed that Cel-targeted proteins disrupt some metabolic biosynthetic processes and promote mitochondrial dysfunction. Ultimately, Cel aggravated kidney cell apoptosis. These cumulative results deliver an insight into the potential mechanisms of Cel-caused nephrotoxicity. They may also facilitate development of antagonistic drugs to mitigate the harmful effects of Cel on the kidneys and improve its clinical applications.© The author(s).