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Ursolic acid derivative UA312 ameliorates ionizing radiation-induced cardiotoxicity and neurodevelopmental toxicity in zebrafish via targeting chrna3 and grik5

Acta Pharmacologica Sinica volume 46, pages 2677–2692 (2025)Cite this article

Abstract

The biological damage caused by ionizing radiation (IR) depends not only on the time and doses of exposure to tissue components but also on the developmental state of the cells. Currently, amifostine is the only radiation-protective agent used for clinical indications related to radiation therapy, but this compound has multiple drawbacks including high toxicity, short half-life and no protective effect on the nervous system. Ursolic acid (UA), a natural pentacyclic triterpenoid that exhibits multiple protective effects including anti-inflammatory, anticarcinogenic, and antioxidant effects. Due to its poor solubility and bioavailability, UA is mostly administered with liposomes. In this study we investigated the impact of UA312, an optimized derivative of UA, on radiation-induced developmental toxicity in zebrafish embryos and larvae. Embryo and larvae survival were observed at 4, 24, 48, and 72 hpf. UA312 was administered at 3 hpf, while embryos were irradiated with 6 Gy of γ-irradiation (dose rate: 0.88 Gy/min) at 4 hpf, then the embryos were moved to a fresh buffer. We determined that 40 µM of UA312 was a safe concentration for zebrafish embryos and larvae. We found that treatment with UA312 (40 µM) restored IR-induced early developmental dysplasia of the zebrafish embryos and larvae. Transcriptomic analysis revealed that exposure to IR inhibited multiple pathways related to neurodevelopment and cardiomyocyte function in zebrafish, which were validated by assessing abnormal cardiac morphology, variations in neurotransmitter levels and alterations in locomotor behavior; and that UA312 treatment ameliorated these alterations. We demonstrated that UA312 treatment significantly reversed the related signaling pathways by targeting chrna3 and grik5. In conclusion, this study identified a promising radioprotective drug, UA312, which alleviates IR-induced cardiotoxicity and neurodevelopmental toxicity in zebrafish by targeting chrna3 and grik5. UA312 may be developed as a novel radioprotective agent against acute IR damage in humans.

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Fig. 1: UA312 is safe and less toxic for zebrafish embryos and larvae.
Fig. 2: UA312 significantly improved IR-induced developmental toxicity in zebrafish embryos and larvae.
Fig. 3: Transcriptome analysis predicted that UA312 mediates cardiac protection and neuroprotection after IR damage.
Fig. 4: UA312 alleviated IR-induced cardiac damage in zebrafish.
Fig. 5: UA312 altered IR-reduced motor behavior in zebrafish larvae.
Fig. 6: UA312 improved the cardiac protection and neuroprotection function of IR damage by targeting chrna3 and grik5.
Fig. 7: UA312 improved the cardiac protection and neuroprotection function of IR damage in mice.
Fig. 8: UA312 protects zebrafish from IR by targeting chran3 and grik5 to improve cardiac toxicity and neurological damage.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (82202950, 82104012 and 82303681), the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2021-I2M-1-042), the Chinese Academy of Medical Sciences Innovation Fund for National Medical Health Science and Technology Platform (2022-I2M-2-003), and Natural Science Foundation of Tianjin City (24JCQNJC01100).

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  1. These authors contributed equally: Fei-fei Xu, Yue Shang, Hui-qiang Wei, Wei-ying Zhang.

Authors and Affiliations

  1. Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300192, China

    Fei-fei Xu, Yue Shang, Hui-qiang Wei, Shu-qin Zhang, Yan-li Li, Hai-hua Shang, Wen-bin Hou, Wen-feng Gou, Sai-jun Fan & Yi-liang Li

  2. Department of Biochemistry and Molecular Biology, College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Nankai University, Tianjin, 300071, China

    Wei-ying Zhang

  3. Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, 110016, China

    Li-xing Wang & Tong Hu

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Contributions

FFX, YS, HQW, and WYZ designed, conducted, and validated the experiments. FFX and YS drafted the manuscript. HQW and WYZ collected and analyzed the data. LXW and TH performed zebrafish feeding and embryo collection. SQZ, YLL, HHS, and WBH involved in regular discussions and manuscript revisions. WFG, SJF, and YLL designed, reviewed and revised the paper. All the authors revised and approved the manuscript. FFX, HQW, WFG, SJF, and YLL provided funding support.

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Correspondence to Wen-feng Gou, Sai-jun Fan or Yi-liang Li.

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Xu, Ff., Shang, Y., Wei, Hq. et al. Ursolic acid derivative UA312 ameliorates ionizing radiation-induced cardiotoxicity and neurodevelopmental toxicity in zebrafish via targeting chrna3 and grik5. Acta Pharmacol Sin 46, 2677–2692 (2025). https://doi.org/10.1038/s41401-025-01564-0

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