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Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
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Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics

Published on: March 15, 2024

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Artemisitene triggers calcium-dependent ferroptosis by disrupting the LSH-EWSR1 interaction in colorectal cancer

Ling Zhu1, Qimei Tan1, Yuxia Wang1

  • 1Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, China.

Redox Biology
|December 3, 2025
PubMed

Insights

Artemisitene (ATT) triggers calcium-dependent ferroptosis in colorectal cancer (CRC) by targeting lymphoid-specific helicase (LSH). This novel mechanism offers a promising therapeutic strategy for drug-resistant CRC.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Colorectal cancer (CRC) presents a significant global health challenge due to its molecular heterogeneity and drug resistance.
  • Ferroptosis, a form of regulated cell death, is a promising therapeutic strategy for CRC, exploiting cancer cells' iron dependency and oxidative vulnerability.
  • Current methods to induce ferroptosis are limited, primarily targeting antioxidant systems or iron metabolism.

Purpose of the Study:

  • To investigate artemisitene (ATT), a natural sesquiterpene, as a potential therapeutic agent for colorectal cancer.
  • To elucidate the mechanism by which ATT promotes ferroptosis in CRC cells.
  • To identify novel therapeutic targets and strategies for CRC treatment.

Main Methods:

  • Integrative transcriptomics to identify molecular targets of ATT.
  • Biochemical assays to confirm protein-protein interactions and covalent binding.
  • Cellular assays to assess ferroptosis induction, calcium levels, fatty acid composition, and cell viability.
  • Pharmacological inhibition and genetic manipulation of key signaling pathways.

Main Results:

  • Artemisitene (ATT) promotes calcium-dependent ferroptosis in CRC cells.
  • ATT represses cytochrome P450 family 24 subfamily A member 1 (CYP24A1) expression, leading to calcium overload.
  • Calcium overload downregulates stearoyl-CoA desaturase (SCD) via the CAMKK2/AMPK/SREBF1 axis, increasing oxidizable fatty acids and sensitizing cells to lipid peroxidation.
  • ATT covalently binds to lymphoid-specific helicase (LSH) at Cys205, disrupting its interaction with EWSR1 and suppressing CYP24A1 transcription.

Conclusions:

  • ATT acts as a CRC therapeutic by inducing calcium-driven ferroptosis through the LSH/CYP24A1/SCD axis.
  • Targeting this axis represents a potent, mechanism-based therapeutic strategy for colorectal cancer.
  • ATT demonstrates potential as a novel, natural product-derived therapeutic agent for CRC.
Keywords:
ArtemisiteneCYP24A1Calcium-dependent ferroptosisColorectal cancerLSHLSH-EWSR1 interaction

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