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<p>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 <i>GPX4</i>, <i>xCT</i>, <i>FSP1</i>, and <i>ATF4</i>; MitoTEMPO rescued cells, implicating mitochondrial ROS. Ferroptosis induction reduced HIF-1α expression/nuclear localization and decreased <i>HIF-1α</i>/<i>VEGF</i>/<i>SOX2</i>/<i>NRF2</i> in tumor tissue, supporting therapeutic potential.</p>

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Ferroptosis-induced oxidative stress in therapy-resistant glioblastoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月26日

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  • 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

摘要

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.