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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Experimental Pharmacology and Drug Discovery
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1464525
This article is part of the Research Topic Organoids for Drug Discovery View all 7 articles

Celastrol reduces cisplatin-induced nephrotoxicity by downregulating SNORD3A level in kidney organoids derived from human iPSCs

Provisionally accepted
Chongyang Shen Chongyang Shen 1Qizheng Wang Qizheng Wang 2Xun Ye Xun Ye 1*Yi Zhou Yi Zhou 3*Huayang Xing Huayang Xing 3Chunjie Wu Chunjie Wu 1*Mingliang You Mingliang You 3*
  • 1 Chengdu University of Traditional Chinese Medicine, Chengdu, China
  • 2 Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences (CAS), Guangzhou, Guangdong Province, China
  • 3 Hangzhou aimingmed organoids bank, HANGZHOU, China

The final, formatted version of the article will be published soon.

    Background: Celastrol, an active ingredient derived from Tripterygium wilfordii Hook F, has shown therapeutic potential for various kidney renal diseases. The kidney protective activity of celastrol is mainly exerted through anti-inflammatory, and antioxidant effects. However, celastrol causes dose-dependent kidney toxicity, which results in increased risks of mortality among patients. This study aimed to develop a kidney organoid-based prediction system to assess the safety and efficacy of celastrol in reducing cisplatin-induced nephrotoxicity. Methods: We investigated the ability of celastrol to reduce cisplatin-induced nephrotoxicity using kidney organoids. Kidney organoids were cultured and characterized, exhibiting renal tubular and glomerular structures and expressing specific kidney markers such as NPHS1, CD31, LTL, and SLC12A1. Data were obtained from in vitro experiments in which kidney organoids were exposed to therapeutically relevant concentrations or a toxic dosing profile of cisplatin and celastrol, to assess their impact on cell viability using flow cytometry and Acridine Orange/Propidium Iodide (AO/PI) staining. In addition, RNA-seq analyses were performed to determine the mechanisms of celastrol function in the kidney. Results: Kidney organoids exposed to 50 µM cisplatin showed significantly increased cell death (only 0.37% cells with normal cell structure), whereas celastrol under 5 µM (56% cells with normal cell structure) showed significantly less nephrotoxicity than cisplatin. The protective effects of celastrol against cisplatin-induced nephrotoxicity were further investigated by treating the organoids with both compounds. The results demonstrated that 2 µM celastrol reduced cisplatin-induced nephrotoxicity by downregulating SNORD3A and HIST1H3A gene levels.This study highlights the potential of celastrol as a protective compound against cisplatin-induced kidney damage and emphasizes the importance of using advanced models, such as iPSC-derived kidney organoids, to predict therapeutic effect and nephrotoxic concentrations of novel drugs.

    Keywords: Celastrol, kidney organoids, nephrotoxicity, Cisplatin, SNORD3A

    Received: 14 Jul 2024; Accepted: 13 Jan 2025.

    Copyright: © 2025 Shen, Wang, Ye, Zhou, Xing, Wu and You. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Xun Ye, Chengdu University of Traditional Chinese Medicine, Chengdu, China
    Yi Zhou, Hangzhou aimingmed organoids bank, HANGZHOU, China
    Chunjie Wu, Chengdu University of Traditional Chinese Medicine, Chengdu, China
    Mingliang You, Hangzhou aimingmed organoids bank, HANGZHOU, China

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.