Ferroptosis-induced oxidative stress in therapy-resistant glioblastoma.

IF 10.4 2区生物学 Q1 CELL BIOLOGY

Cell Death Discovery Pub Date : 2026-06-26 DOI:10.1038/s41420-026-03227-3

Sofia Remedia, Cristina Martelli, Marcella Bonanomi, Bruno Giovanni Galuzzi, Francesca Servidio, Clarissa Gervasoni, Martina Nespoli, Chiara Pellizzer, Alessandro Giammona, Daniela Gaglio, Daniele Capitanio, Gloria Bertoli, Luisa Ottobrini, Alessia Lo Dico

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引用次数: 0

Abstract

Temozolomide (TMZ) resistance remains a major obstacle in glioma treatment. Ferroptosis, an iron-dependent, lipid peroxidation-driven regulated cell death, represents a promising alternative strategy. We investigated molecular determinants of ferroptosis sensitivity in TMZ-resistant glioma, focusing on HIF-1α and oxidative stress. One TMZ-sensitive (U251) and three TMZ-resistant (T98, U118, LN18) cell lines were treated with ferroptosis inducers (Erastin, FIN56, RSL3). Viability, ROS (total and mitochondrial), lipid peroxidation, and ferroptosis-related gene/protein expression were assessed. MitoTEMPO and deferoxamine (DFX) were used to probe mitochondrial ROS and iron dependence, respectively. Integrated metabolomic-proteomic analyses and an orthotopic U118-Luc model supported in vitro findings. Ferroptosis inducers reduced viability and bypassed TMZ resistance in vitro and suppressed tumor growth in vivo with partial body-weight loss. Resistant cells displayed high HIF-1α with elevated GSH/NRF2 activity and reduced lipid peroxidation. Treatments increased oxidative stress and downregulated GPX4, xCT, FSP1, and ATF4; MitoTEMPO rescued cells, implicating mitochondrial ROS. Ferroptosis induction reduced HIF-1α expression/nuclear localization and decreased HIF-1α/VEGF/SOX2/NRF2 in tumor tissue, supporting therapeutic potential.

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抗治疗胶质母细胞瘤中铁中毒诱导的氧化应激。

替莫唑胺（TMZ）耐药性仍然是胶质瘤治疗的主要障碍。铁死亡是一种铁依赖性、脂质过氧化驱动的调节细胞死亡，代表了一种有希望的替代策略。我们研究了tmz耐药胶质瘤中铁上吊敏感性的分子决定因素，重点是HIF-1α和氧化应激。1株tmz敏感细胞株（U251）和3株tmz耐药细胞株（T98、U118、LN18）分别用铁凋亡诱导剂（Erastin、FIN56、RSL3）处理。评估细胞活力、活性氧（总ROS和线粒体ROS）、脂质过氧化和凋亡相关基因/蛋白表达。MitoTEMPO和去铁胺（DFX）分别用于检测线粒体ROS和铁依赖性。综合代谢组学-蛋白质组学分析和原位U118-Luc模型支持体外研究结果。下垂铁诱导剂在体外降低了肿瘤的生存能力，绕过了TMZ耐药性，在体内抑制了肿瘤的生长，并伴有部分体重减轻。耐药细胞显示高HIF-1α， GSH/NRF2活性升高，脂质过氧化降低。处理增加了氧化应激，下调了GPX4、xCT、FSP1和ATF4；MitoTEMPO挽救细胞，暗示线粒体ROS。铁下垂诱导降低肿瘤组织中HIF-1α表达/核定位，降低HIF-1α/VEGF/SOX2/NRF2，支持治疗潜力。

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.