HADHA-mediated regulation of JAK/STAT3 signaling in glioblastoma: a metabolic-epigenetic axis.

IF 7 2区生物学 Q1 CELL BIOLOGY

Cell Death Discovery Pub Date : 2025-08-01 DOI:10.1038/s41420-025-02660-0

Kan Wang, Yifei Xiao, Jinxin Wan, Yuanqi Chu, Ruipeng Zheng, Fengjun Lv, Guang Yang, Mingchun Yang, Haitao Ge, Yuwen Song, Yu Cheng

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Abstract

Astract: Glioblastoma multiforme (GBM) is one of the most aggressive forms of brain cancer, characterized by rapid growth and resistance to conventional therapies. This study investigates the role of HADHA, a key enzyme in fatty acid β-oxidation, in the progression of GBM. we show that the overexpression of HADHA in GBM correlates with a poor prognosis in patients and plays a role in promoting tumor growth and invasion. Mechanistically, HADHA regulates the JAK/STAT3 signaling pathway through modulation of H3K27ac histone acetylation. Knockdown of HADHA results in decreased acetyl-CoA levels, leading to reduced H3K27ac modification and subsequent inhibition of JAK/STAT3 activation. Furthermore, we show that the small molecule JIB-04, which targets HADHA, inhibits GBM cell proliferation and invasion both in vitro and in vivo. Our findings highlight the importance of targeting metabolic enzymes in cancer therapy and suggest that HADHA could represent a potential new therapeutic target for GBM. By targeting the metabolic-epigenetic pathway, this strategy presents a promising approach for treating this devastating disorder.

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胶质母细胞瘤中hadha介导的JAK/STAT3信号调控：代谢-表观遗传轴。

摘要：多形性胶质母细胞瘤（GBM）是最具侵袭性的脑癌之一，其特点是快速生长和对常规治疗具有耐药性。本研究探讨脂肪酸β-氧化的关键酶HADHA在GBM进展中的作用。我们发现，在GBM中，HADHA的过表达与患者预后不良相关，并在促进肿瘤生长和侵袭方面发挥作用。在机制上，HADHA通过调节H3K27ac组蛋白乙酰化调节JAK/STAT3信号通路。敲低HADHA导致乙酰辅酶a水平降低，导致H3K27ac修饰减少，进而抑制JAK/STAT3的激活。此外，我们发现靶向HADHA的小分子JIB-04在体外和体内都能抑制GBM细胞的增殖和侵袭。我们的研究结果强调了靶向代谢酶在癌症治疗中的重要性，并表明HADHA可能代表了GBM的潜在新治疗靶点。通过靶向代谢-表观遗传途径，这种策略为治疗这种毁灭性疾病提供了一种有希望的方法。

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

Cell Death Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology

CiteScore

8.30

自引率

1.40%

发文量

468

审稿时长

9 weeks

期刊介绍： Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary. Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.