Lan Jin, Zhang Weili, Zeng Kaixuan, Li Cong, He Jiahua, Li Xinyue, Yang Rong, Chi Jun, Hong Zhigang, Wang Weifeng, Zhou Chi, Xiao Binyi, Fan Wenhua, Lin Junzhong, Ou Qingjian, Fang Yujing, Pan Zhizhong, Peng Jianhong, Li Weihao, Wu Xiaojun
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China.
Clin Transl Med. 2025 Sep;15(9):e70438. doi: 10.1002/ctm2.70438.
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.
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.
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.
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.
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.
伊马替尼已广泛应用于胃肠道间质瘤，显著改善了胃肠道间质瘤患者的预后，但约一半的患者会产生获得性治疗耐药性，这凸显了新型治疗策略的紧迫性。
采用多种生物信息学工具和实验室实验、RNA测序、动物模型和热蛋白质组分析方法来验证我们的发现，并研究β-榄香烯的抗肿瘤作用。
我们发现伊马替尼耐药的胃肠道间质瘤与铁死亡活性的负调控有关，诱导铁死亡可增强耐药细胞对伊马替尼的敏感性。此外，我们发现β-榄香烯通过诱导铁死亡增强伊马替尼耐药胃肠道间质瘤细胞对伊马替尼的敏感性。而且，与单药治疗相比，β-榄香烯与伊马替尼联合治疗在体外和体内均显示出显著增强的抗肿瘤疗效。机制上，β-榄香烯特异性靶向N6AMT1，抑制其转录抑制功能并激活核因子红细胞2相关因子2（NRF2）-血红素加氧酶1（HMOX1）信号通路以诱导铁死亡。
β-榄香烯可靶向N6AMT1，并通过增加NRF2和HMOX1的表达促进铁死亡。这些发现表明β-榄香烯是提高伊马替尼在胃肠道间质瘤中敏感性的一种前瞻性治疗策略。
l伊马替尼耐药与胃肠道间质瘤中的铁死亡活性相关。lβ-榄香烯与伊马替尼联合可在体内外有效治疗胃肠道间质瘤。lβ-榄香烯通过铁死亡促进胃肠道间质瘤对伊马替尼的敏感性。lN6AMT1是β-榄香烯的潜在靶点。lβ-榄香烯通过NRF2/HMOX1轴靶向N6AMT1以促进伊马替尼耐药胃肠道间质瘤细胞对伊马替尼的敏感性。
