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<p>Ferroptosis, a form of iron-dependent cell death, is emerging as a potential therapeutic target due to its ability to inhibit tumor growth and enhance immune responses. However, the mechanisms regulating ferroptosis and tumor metastasis, particularly in colorectal cancer (CRC), remain poorly understood. In this study, bioinformatics analysis identified MC1R as a key regulator of ferroptosis-related genes. In vitro experiments showed MC1R overexpression in CRC cell lines promotes cell proliferation and migration while inhibiting ferroptosis via downregulating ACSL4 expression, with opposite effects seen in MC1R knockdown. In vivo experiments also found MC1R-knockdown CRC cells resulted in xenograft tumors with lower volume and weight. Mechanistically, MC1R activates the Notch signaling pathway, leading to ACSL4 inhibition, which inhibits ferroptosis and, in turn, cell growth and migration. High MC1R expression in CRC correlates with poor prognosis and is negatively associated with ferroptosis levels. Targeting MC1R could offer a novel strategy to enhance ferroptosis in CRC, potentially improving patient outcomes. This study elucidates the complex interactions between MC1R, Notch signaling, and ferroptosis, providing insights for developing targeted therapies in CRC.</p>

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MC1R contributes to ferroptosis resistance and tumor aggressiveness in colorectal cancer by activating Notch signaling

  • 期刊论文

  • 发表日期：

    2025年10月15日

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  • Xiangwei Zeng,
  • Lujian Jiang,
  • Huili Li,
  • Jiamou Wang,
  • Xuan He

摘要

Ferroptosis, a form of iron-dependent cell death, is emerging as a potential therapeutic target due to its ability to inhibit tumor growth and enhance immune responses. However, the mechanisms regulating ferroptosis and tumor metastasis, particularly in colorectal cancer (CRC), remain poorly understood. In this study, bioinformatics analysis identified MC1R as a key regulator of ferroptosis-related genes. In vitro experiments showed MC1R overexpression in CRC cell lines promotes cell proliferation and migration while inhibiting ferroptosis via downregulating ACSL4 expression, with opposite effects seen in MC1R knockdown. In vivo experiments also found MC1R-knockdown CRC cells resulted in xenograft tumors with lower volume and weight. Mechanistically, MC1R activates the Notch signaling pathway, leading to ACSL4 inhibition, which inhibits ferroptosis and, in turn, cell growth and migration. High MC1R expression in CRC correlates with poor prognosis and is negatively associated with ferroptosis levels. Targeting MC1R could offer a novel strategy to enhance ferroptosis in CRC, potentially improving patient outcomes. This study elucidates the complex interactions between MC1R, Notch signaling, and ferroptosis, providing insights for developing targeted therapies in CRC.