KSRP-dependent immunogenic cell death induced by pyridazinone derivative IMB5036 drives antitumor immunity in neuroblastoma

IF 3 4区生物学 Q1 Biochemistry, Genetics and Molecular Biology

FEBS Letters Pub Date : 2026-10-12 Epub Date: 2026-05-26 DOI:10.1002/1873-3468.70364

Yanqun Dong, Yanfeng Xu, Junyi Zhang, Hanyu Hong, Lingli Gao, Hanrui Wei, Yijia Zheng, Xing Lv, Yan-Bo Zheng, Jigang Yang, Jian-Hua Gong

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引用次数: 0

Abstract

The small-molecule pyridazinone derivative IMB5036 (IMB) exhibits significant cytotoxicity against multiple cancer cell lines, and KH-type splicing regulatory protein (KSRP) is confirmed as its direct binding partner. However, KSRP's functional role in neuroblastoma (NB) and the mechanism mediating IMB's antitumor effects remain unclear. This study analyzed public tumor databases and found KSRP expression negatively correlates with NB patients' median survival. Experiments showed IMB induces NB cell pyroptosis, immunogenic cell death (ICD, with calreticulin exposure), and cGAS-STING activation (to boost antitumor immunity), while CRISPR-Cas9-mediated KSRP knockout notably attenuates these effects. Transcriptome sequencing further confirmed KSRP mediates IMB's regulation of HSPA6/RSAD2. This study clarifies KSRP-dependent ICD drives NB antitumor immunity, providing a basis for KSRP-targeted NB immunotherapies.

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吡嗪酮衍生物IMB5036诱导的ksrp依赖性免疫原性细胞死亡驱动神经母细胞瘤的抗肿瘤免疫。

小分子吡嗪酮衍生物IMB5036 （IMB）对多种癌细胞表现出明显的细胞毒性，kh型剪接调节蛋白（KSRP）被证实是其直接结合伙伴。然而，KSRP在神经母细胞瘤（NB）中的功能作用以及介导IMB抗肿瘤作用的机制尚不清楚。本研究分析了公共肿瘤数据库，发现KSRP表达与NB患者的中位生存期呈负相关。实验表明，IMB诱导NB细胞焦亡、免疫原性细胞死亡（ICD， calreticulin暴露）和cGAS-STING激活（以增强抗肿瘤免疫），而crispr - cas9介导的KSRP敲除显著减弱了这些作用。转录组测序进一步证实KSRP介导IMB对HSPA6/RSAD2的调控。本研究阐明了ksrp依赖性ICD驱动NB抗肿瘤免疫，为ksrp靶向NB免疫治疗提供了基础。

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

FEBS Letters 生物-生化与分子生物学

CiteScore

7.00

自引率

2.90%

发文量

303

审稿时长

1.0 months

期刊介绍： FEBS Letters is one of the world''s leading journals in molecular biology and is renowned both for its quality of content and speed of production. Bringing together the most important developments in the molecular biosciences, FEBS Letters provides an international forum for Minireviews, Research Letters and Hypotheses that merit urgent publication.