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Background <p>Ferroptosis is an iron-dependent form of regulated necrosis driven by unchecked lipid peroxidation. Its relevance to cancer biology has become increasingly evident.&#xa0;Our long-standing ferric nitrilotriacetate (Fe-NTA) rat model exemplifies how chronic Fenton chemistry induces DNA damage, genomic instability, and selection of ferroptosis-resistant malignant clones, underscoring the central role of iron in carcinogenesis.</p> Recent Advances <p>Cancer cells acquire multiple adaptations to maintain iron addiction while escaping ferroptotic pressure, including reinforcement of the xCT–CD44v axis, GPX4 and FSP1 activities, NRF2-mediated antioxidant programs, and mitochondrial remodeling. Ferroptosis can also act as an immunogenic cell death modality by releasing oxidized phospholipids and DAMPs that activate dendritic cells and CD8⁺ T cells, a process termed immunoferroptosis. Low-temperature plasma (LTP) has emerged as a unique modality capable of producing reactive oxygen and nitrogen species to selectively trigger ferroptosis in iron-loaded cancer cells while sparing normal tissues.</p> Diagnostic and Genetic Context <p>HNE-modified proteins currently serve as robust markers of lipid peroxidation in FFPE samples, whereas visualization of catalytic Fe(II)—the executer of ferroptosis—requires frozen tissues or live-cell imaging. Cancer-prone hereditary syndromes such as BRCA1/2 deficiency and Fanconi anemia exhibit ferroptosis resistance, linking defective genome maintenance to impaired ferroptotic signaling.</p> Outlook <p>Ferroptosis functions both as an intrinsic tumor-suppressive mechanism and a tractable therapeutic vulnerability. Harnessing ferroptosis offers a promising strategy for targeting iron-addicted cancers.</p>

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Ferroptosis and cancer: when iron turns against tumors

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月25日

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  • Shinya Toyokuni,
  • Yingyi Kong,
  • Yuki Maeda,
  • Qinying Lyu,
  • Yuuki Ohara,
  • Kotaro Sato,
  • Yashiro Motooka,
  • Kae Nakamura,
  • Hiromasa Tanaka

摘要

Background

Ferroptosis is an iron-dependent form of regulated necrosis driven by unchecked lipid peroxidation. Its relevance to cancer biology has become increasingly evident. Our long-standing ferric nitrilotriacetate (Fe-NTA) rat model exemplifies how chronic Fenton chemistry induces DNA damage, genomic instability, and selection of ferroptosis-resistant malignant clones, underscoring the central role of iron in carcinogenesis.

Recent Advances

Cancer cells acquire multiple adaptations to maintain iron addiction while escaping ferroptotic pressure, including reinforcement of the xCT–CD44v axis, GPX4 and FSP1 activities, NRF2-mediated antioxidant programs, and mitochondrial remodeling. Ferroptosis can also act as an immunogenic cell death modality by releasing oxidized phospholipids and DAMPs that activate dendritic cells and CD8⁺ T cells, a process termed immunoferroptosis. Low-temperature plasma (LTP) has emerged as a unique modality capable of producing reactive oxygen and nitrogen species to selectively trigger ferroptosis in iron-loaded cancer cells while sparing normal tissues.

Diagnostic and Genetic Context

HNE-modified proteins currently serve as robust markers of lipid peroxidation in FFPE samples, whereas visualization of catalytic Fe(II)—the executer of ferroptosis—requires frozen tissues or live-cell imaging. Cancer-prone hereditary syndromes such as BRCA1/2 deficiency and Fanconi anemia exhibit ferroptosis resistance, linking defective genome maintenance to impaired ferroptotic signaling.

Outlook

Ferroptosis functions both as an intrinsic tumor-suppressive mechanism and a tractable therapeutic vulnerability. Harnessing ferroptosis offers a promising strategy for targeting iron-addicted cancers.