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

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. KEY POINTS: l Imatinib resistance is associated with ferroptosis activity in GIST. l Combination of β-elemene and imatinib effectively treats gastrointestinal stromal tumours both in vivo and in vitro. l β-elemene promotes imatinib sensitivity in GIST through ferroptosis. l N6AMT1 is a potential target of β-elemene. l β-elemene targets N6AMT1 to promote imatinib sensitivity in imatinib-resistant GIST cells via the NRF2/HMOX1 axis.