Wedelolactone induces pyroptosis to suppress retinoblastoma by inhibiting the Nrf2/Keap1 signaling pathway.

IF 3.5 4区医学 Q2 ONCOLOGY

Medical Oncology Pub Date : 2025-08-29 DOI:10.1007/s12032-025-02916-w

Yizhou Jiang, Hua Jiang, Guitao Wu, Ningdong Pang, Chuanqiang Niu, Zhouping Wang, Haibo Li

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引用次数: 0

Abstract

Background: Retinoblastoma is an intraocular malignancy with limited therapeutic options, imposing a severe health burden on young patients. Wedelolactone (WDL), a natural product from E. prostrata, possesses an anti-retinoblastoma activity, with the underlying regulatory mechanism remaining unknown.

Methods: Retinoblastoma cell lines and xenograft nude mouse models were treated with WDL and RTA-408, an agonist for nuclear factor-erythroid 2-related factor 2 (Nrf2). Western blotting was conducted to determine the protein expression levels of kelch-like ECH-associated protein 1 (Keap1) and Nrf2. We performed the cell counting kit-8 assay, the 5-ethynyl-2-deoxyuridine staining, and flow cytometry to detect cell viability, proliferation, and apoptosis, respectively. The tumor progression in vivo was evaluated via the measurement of volume, weight, and proliferation levels of solid tumors. Monosodium urate crystal was applied to activate pyroptosis which was assessed by the expression detection of pyroptosis-related indicators.

Results: WDL treatment elevated the expression of Keap1 and reduced the level of Nrf2. RTA-408 suppressed WDL-induced pyroptosis of retinoblastoma cells and reversed the effect of WDL on inhibiting retinoblastoma cell proliferation, promoting tumor cell apoptosis, and repressing the growth of solid tumors of the xenograft models. In addition, monosodium urate-induced pyroptosis partially restored the anti-retinoblastoma effect of WDL impaired by RTA-408.

Conclusion: WDL triggers pyroptosis by inhibiting the Nrf2/Keap1 signaling pathway to exert anti-retinoblastoma effects.

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维地内酯通过抑制Nrf2/Keap1信号通路诱导焦亡抑制视网膜母细胞瘤。

背景：视网膜母细胞瘤是一种治疗选择有限的眼内恶性肿瘤，给年轻患者带来了严重的健康负担。维地内酯（Wedelolactone， WDL）是一种天然产自前列腺的物质，具有抗视网膜母细胞瘤的活性，其作用机制尚不清楚。方法：用WDL和Nrf2受体激动剂RTA-408治疗视网膜母细胞瘤细胞系和异种移植裸鼠模型。Western blotting检测kelch-like ECH-associated protein 1 （Keap1）和Nrf2蛋白表达水平。我们分别用细胞计数试剂盒-8、5-乙基-2-脱氧尿苷染色和流式细胞术检测细胞活力、增殖和凋亡。通过测量实体瘤的体积、重量和增殖水平来评估肿瘤在体内的进展。应用尿酸钠晶体激活焦亡，通过检测焦亡相关指标的表达来评价焦亡效果。结果：WDL可提高Keap1表达，降低Nrf2水平。RTA-408抑制WDL诱导的视网膜母细胞瘤细胞凋亡，逆转WDL抑制视网膜母细胞瘤细胞增殖、促进肿瘤细胞凋亡、抑制异种移植模型实体瘤生长的作用。此外，尿酸钠诱导的焦亡部分恢复了RTA-408损伤的WDL抗视网膜母细胞瘤的作用。结论：WDL通过抑制Nrf2/Keap1信号通路触发焦亡，发挥抗视网膜母细胞瘤作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Medical Oncology 医学-肿瘤学

CiteScore

4.20

自引率

2.90%

发文量

259

审稿时长

1.4 months

期刊介绍： Medical Oncology (MO) communicates the results of clinical and experimental research in oncology and hematology, particularly experimental therapeutics within the fields of immunotherapy and chemotherapy. It also provides state-of-the-art reviews on clinical and experimental therapies. Topics covered include immunobiology, pathogenesis, and treatment of malignant tumors.