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2000
Volume 25, Issue 10
  • ISSN: 1568-0096
  • E-ISSN: 1873-5576

Abstract

Background

Ferroptosis is closely related to radiotherapy resistance in multiple cancers. Herein, the role of microsomal glutathione S-transferase 1 (MGST1) in regulating ferroptosis and radiotherapy resistance in non-small cell lung cancer (NSCLC) was investigated.

Methods

Radiation-resistant NSCLC cells (NCI-1299-IR and HCC827-IR cells) were established. After exposure to X-ray, cell proliferation and survival were assessed by colony formation assay and CCK-8 assay, and lipid ROS level was examined by the fluorophore BODIPY™ 581/591 C11. MDA, GSH, and Fe2+ levels were measured by ELISA kits. The molecular interaction was analyzed using ChIP and MSP assays.

Results

Our results showed that RSL3 treatment greatly enhanced the radiotherapy sensitivity of NCI-1299-IR and HCC827-IR cells. It was subsequently revealed that MGST1 was highly expressed in NCI-1299-IR and HCC827-IR cells than its parent cells, and silencing of MGST1 reduced radioresistance of NCI-1299-IR and HCC827-IR cells by facilitating ferroptosis. Mechanistically, MGST1 knockdown greatly reduced HO-1 and DNMT1/3A protein levels, leading to reduced DNA methylation on the ALOX15 promoter region, thereby epigenetically upregulating ALOX15 expression. As expected, the promoting effects of MGST1 silencing on radiosensitivity and ferroptosis in radiation-resistant NSCLC cells were strikingly eliminated by ALOX15 knockdown.

Conclusion

MGST1 knockdown epigenetically enhanced radiotherapy sensitivity of NCSLC cells by promoting ALOX15-mediated ferroptosis through regulating the HO-1/DNMT1 pathway.

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2025-12-24

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Targeting MGST1 Makes Non-Small Cell Lung Cancer Cells Sensitive to Radiotherapy by Epigenetically Enhancing ALOX15-Mediated Ferroptosis
Curr. Cancer Drug Targets< 25, 1271 (2025); https://doi.org/10.2174/0115680096317925240820053934
/content/journals/ccdt/10.2174/0115680096317925240820053934
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  • Article Type:     Research Article
Keyword(s): ALOX15; ferroptosis; HO-1/DNMT1 pathway; MGST1; Non-small cell lung cancer; radioresistance

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