Ge Xiyang, Yin Yiyan, Wang Xiaoni, Li Xiang, Ouyang Jin, Na Na
Key Laboratory of Radiopharmaceuticals, College of Chemistry, Beijing Normal University Beijing 100875 China
State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences Beijing 100700 China.
Chem Sci. 2025 Jul 5. doi: 10.1039/d5sc02512e.
Ferroptosis exhibits promising potential in cancer therapy lipid peroxidation (LPO) accumulation, while its therapeutic efficacy is normally limited by inadequate ROS production and adverse effects on normal tissues. Here, a TME-activated synthesis of a single-site catalyst (Fe(ii)-PW) is reported, which triggers ferroptosis by mimicking natural enzyme activities of NADPH oxidase (NOX) and lipoxygenase (LOX) cascade reactions. Upon degradation of the nanocarrier by the overexpressed GSH in an acidic TME, Fe(ii)-PW is obtained through the coordination of Fe into lacunary phosphotungstic acid (PW). Subsequently, Fe(ii)-PW catalyzes NADPH depletion and O˙ generation through a NOX-like process. This facilitates the formation of high-valent Fe(iv)[double bond, length as m-dash]O-PW, initiating cascade reactions to generate lipid radicals through hydrogen atom transfer based on LOX-like activity. Thus, Fe(ii)-PW synergistically accelerates LPO accumulation and antioxidant inhibitions, effectively inducing ferroptosis for cancer therapy. Notably, Fe(ii)-PW is degraded into low-toxic debris in normal organs, reducing side effects after treatment. Significantly, the whole process is well confirmed by comprehensive characterization studies including online monitoring ambient mass spectrometry. This work not only reveals a novel ferroptosis-based cancer treatment in a ROS-independent pathway, but also provides a safe therapeutic modality with low toxicity to normal tissues.
铁死亡在癌症治疗中显示出有前景的潜力，其通过脂质过氧化（LPO）积累发挥作用，但其治疗效果通常受到活性氧（ROS）生成不足以及对正常组织的副作用的限制。在此，报道了一种肿瘤微环境（TME）激活的单原子催化剂（Fe(ii)-PW）的合成，其通过模拟烟酰胺腺嘌呤二核苷酸磷酸氧化酶（NOX）和脂氧合酶（LOX）的天然酶活性引发级联反应来触发铁死亡。在酸性TME中，纳米载体被过表达的谷胱甘肽（GSH）降解后，通过Fe与缺位磷钨酸（PW）配位得到Fe(ii)-PW。随后，Fe(ii)-PW通过类似NOX的过程催化烟酰胺腺嘌呤二核苷酸磷酸（NADPH）消耗和氧自由基（O˙）生成。这促进了高价铁（IV）[双键，长度如中划线]氧 - PW的形成，基于类似LOX的活性通过氢原子转移引发级联反应以生成脂质自由基。因此，Fe(ii)-PW协同加速LPO积累和抗氧化抑制，有效诱导铁死亡用于癌症治疗。值得注意的是，Fe(ii)-PW在正常器官中降解为低毒碎片，减少了治疗后的副作用。重要的是，包括在线监测环境质谱在内的综合表征研究充分证实了整个过程。这项工作不仅揭示了一种基于铁死亡的不依赖ROS途径的癌症治疗方法，还提供了一种对正常组织毒性低的安全治疗方式。
