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<p>Triple-negative breast cancer (TNBC) exhibits iron homeostasis that supports tumor growth and proliferation, yet the regulatory mechanisms controlling iron flux remain poorly defined. Here, we identify a ferritinophagic cargo receptor NCOA4 as a novel substrate of the lysine methyltransferase SUV39H2, uncovering a previously unrecognized mechanism that regulates ferritinophagy and ferroptosis. SUV39H2 directly binds and mono-methylates NCOA4 at lysine 356, a modification that reduces NCOA4 stability. Mechanistically, K356 methylation enhances NCOA4 interaction with the E3 ligase HERC2, promoting its ubiquitination and proteasomal degradation. This degradation increases FTH1 stability, suppresses ferritinophagic flux, limits iron release, maintains the high-risk iron homeostasis and ferroptosis resistance, ultimately promoting tumor proliferation and chemoresistance. Conversely, genetic or pharmacologic inhibition of SUV39H2 (OTS186935) inhibit NCOA4 methylation, stabilizes NCOA4 protein, enhances ferritinophagy, and triggers ferroptosis. Furthermore, SUV39H2 inhibition sensitizes TNBC cells to chemotherapy in vitro and in vivo, indicating OTS186935 treatment is a feasible therapeutic strategy. Collectively, the SUV39H2-NCOA4-HERC2 axis as a critical regulatory pathway in iron metabolism and ferroptosis, and highlight inhibition of NCOA4 K356 methylation as a promising therapeutic target in TNBC.</p><p></p>

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SUV39H2-mediated NCOA4 methylation controls ferritinophagy and ferroptosis in triple-negative breast cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月16日

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  • Lingxia Liu,
  • Xinyun Pei,
  • Ding Li,
  • Ying Huo,
  • Zhaoting Wang,
  • Qiu Zhang,
  • Yuan Yue,
  • Bao Deng,
  • Minmin Yu,
  • Tong Xu,
  • Lei Zhong,
  • Xianhui Ruan,
  • Xichuan Li

摘要

Triple-negative breast cancer (TNBC) exhibits iron homeostasis that supports tumor growth and proliferation, yet the regulatory mechanisms controlling iron flux remain poorly defined. Here, we identify a ferritinophagic cargo receptor NCOA4 as a novel substrate of the lysine methyltransferase SUV39H2, uncovering a previously unrecognized mechanism that regulates ferritinophagy and ferroptosis. SUV39H2 directly binds and mono-methylates NCOA4 at lysine 356, a modification that reduces NCOA4 stability. Mechanistically, K356 methylation enhances NCOA4 interaction with the E3 ligase HERC2, promoting its ubiquitination and proteasomal degradation. This degradation increases FTH1 stability, suppresses ferritinophagic flux, limits iron release, maintains the high-risk iron homeostasis and ferroptosis resistance, ultimately promoting tumor proliferation and chemoresistance. Conversely, genetic or pharmacologic inhibition of SUV39H2 (OTS186935) inhibit NCOA4 methylation, stabilizes NCOA4 protein, enhances ferritinophagy, and triggers ferroptosis. Furthermore, SUV39H2 inhibition sensitizes TNBC cells to chemotherapy in vitro and in vivo, indicating OTS186935 treatment is a feasible therapeutic strategy. Collectively, the SUV39H2-NCOA4-HERC2 axis as a critical regulatory pathway in iron metabolism and ferroptosis, and highlight inhibition of NCOA4 K356 methylation as a promising therapeutic target in TNBC.