β-elemene promotes ferroptosis to improve the sensitivity of imatinib in gastrointestinal stromal tumours by targeting N6AMT1

Abstract

Background: Imatinib has been widely used in gastrointestinal stromal tumours and significantly improved the prognosis of GIST patients, but approximately half of patients develop acquired treatment resistance, highlighting the urgency for novel therapeutic strategies.

Methods: A variety of bioinformatic tools and laboratory experiments, RNA sequencing, animal models and the thermal proteome profiling assay were employed to validate our findings and investigate the antitumour effects of β-elemene.

Results: We found that imatinib-resistant GIST was associated with negative regulation of ferroptosis activity, and inducing ferroptosis can enhance the sensitivity of resistant cells to imatinib. Furthermore, we found that β-elemene enhances imatinib sensitivity in imatinib-resistant GIST cells through inducing ferroptosis. Moreover, the combination treatment of β-elemene and imatinib showed significantly increased antitumour efficacy, compared to each monotherapy, both in vitro and in vivo. Mechanistically, β-elemene specifically targets N6AMT1, inhibiting its transcriptional repression function and activating the nuclear factor erythroid 2-related factor 2 (NRF2)-HMOX1 signalling pathway to induce ferroptosis.

Conclusion: Β-elemene can target N6AMT1 and promote ferroptosis by increasing the expression of NRF2 and HMOX1. These findings suggest β-elemene as a prospective therapeutic strategy to improve the sensitivity of imatinib in gastrointestinal stromal tumours.

Keywords

ferroptosis / gastrointestinal stromal tumours / imatinib resistance / ROS / β-elemene

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2025 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.