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Updated: Feb 23, 2026
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
EGLN1/c-Myc Induced Lymphoid-Specific Helicase Inhibits Ferroptosis through Lipid Metabolic Gene Expression Changes
Yiqun Jiang1,2,3, Chao Mao1,2, Rui Yang1,2
1Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008 China.
Abstract:
Ferroptosis is a newly discovered form of non-apoptotic cell death in multiple human diseases. However, the epigenetic mechanisms underlying ferroptosis remain poorly defined. First, we demonstrated that lymphoid-specific helicase (LSH), which is a DNA methylation modifier, interacted with WDR76 to inhibit ferroptosis by activating lipid metabolism-associated genes, including GLUT1, and ferroptosis related genes SCD1 and FADS2, in turn, involved in the Warburg effect. WDR76 targeted these genes expression in dependent manner of LSH and chromatin modification in DNA methylation and histone modification. These effects were dependent on iron and lipid reactive oxygen species. We further demonstrated that EGLN1 and c-Myc directly activated the expression of LSH by inhibiting HIF-1α. Finally, we demonstrated that LSH functioned as an oncogene in lung cancer in vitro and in vivo. Therefore, our study elucidates the molecular basis of the c-Myc/EGLN1-mediated induction of LSH expression that inhibits ferroptosis, which can be exploited for the development of therapeutic strategies targeting ferroptosis for the treatment of cancer.
Insights
Lymphoid-specific helicase (LSH) inhibits ferroptosis, a cell death form, by regulating lipid metabolism and gene expression. This discovery offers new therapeutic targets for cancer treatment.
Area of Science:
- Cell Biology
- Epigenetics
- Cancer Research
Background:
- Ferroptosis is a distinct form of cell death implicated in various diseases.
- The epigenetic regulation of ferroptosis is not well understood.
- Understanding these mechanisms is crucial for developing new therapeutic strategies.
Purpose of the Study:
- To investigate the epigenetic mechanisms controlling ferroptosis.
- To identify key regulators involved in ferroptosis.
- To explore the role of lymphoid-specific helicase (LSH) in cancer.
Main Methods:
- Investigated the interaction between LSH and WDR76.
- Analyzed the impact of LSH on lipid metabolism and ferroptosis-related genes (GLUT1, SCD1, FADS2).
- Examined the role of c-Myc/EGLN1/HIF-1α pathway in regulating LSH expression.
- Assessed LSH function in lung cancer models (in vitro and in vivo).
Main Results:
- LSH, interacting with WDR76, inhibits ferroptosis by activating genes involved in lipid metabolism and the Warburg effect.
- LSH's regulation of gene expression involves DNA methylation and histone modification.
- The c-Myc/EGLN1 pathway directly induces LSH expression by inhibiting HIF-1α.
- LSH acts as an oncogene in lung cancer, promoting tumor growth.
Conclusions:
- Elucidated the molecular basis of LSH-mediated inhibition of ferroptosis.
- Identified a novel regulatory pathway involving c-Myc/EGLN1/HIF-1α and LSH.
- Demonstrated LSH's oncogenic role in lung cancer.
- Highlighted the potential of targeting ferroptosis for cancer therapy.
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