Ferroptosis is an iron-mediated regulated cell death initiated by excessive membrane lipid peroxide accumulation. The intimate interplay between ferroptosis and lipid metabolism suggests that modulating lipid metabolism and activating ferroptosis may represent a broader cancer therapeutic space. Herein, two fibrate lipid-modulating agents, fenofibric acid and ciprofibrate, were employed to functionalize the clinical drug cisplatin through a Pt(IV) prodrug strategy, affording four fibrate-Pt(IV) anticancer prodrugs, compounds 1–4, with prominent anticancer activity and ferroptosis induction. The representative compounds, 1 and 3, exhibited antiproliferative activity up to 140- and 90-fold greater than cisplatin, respectively. Our data demonstrated that fibrate-Pt(IV) prodrugs accumulated in A549 cells much higher than cisplatin, followed by a dramatic decrease in intracellular lipid content, elevated reactive oxygen species (ROS) levels, disruption of the mitochondrial transmembrane potential, and remarkable proliferation inhibition. Moreover, our results revealed that fibrate-Pt(IV) prodrugs not only induced DNA damage, apoptosis, and cell cycle arrest, but also led to increases in lipid peroxides, ferrous ions, and malondialdehyde (MDA), as well as a decrease in glutathione, which triggers ferroptosis by suppressing the system Xc⁻/GSH/GPX4 antioxidant defense axis and stimulation of the iron axis. Our results emphasize that combining lipid metabolism regulation with ferroptosis to develop new platinum-based anticancer agents can produce excellent multi-action anticancer activities, which may represent a promising cancer treatment modality.

中文翻译：

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使用多功能贝特-Pt(IV)前药破坏脂质代谢诱导铁死亡用于癌症治疗

铁死亡是一种由铁介导的调节性细胞死亡，由过量的膜脂质过氧化物积累引发。铁死亡和脂质代谢之间的密切相互作用表明，调节脂质代谢和激活铁死亡可能代表更广泛的癌症治疗空间。本文采用两种贝特类调脂剂非诺贝特酸和环丙贝特，通过 Pt( IV ) 前药策略对临床药物顺铂进行功能化，得到四种贝特类-Pt( IV ) 抗癌前药，化合物1–4，具有显着的抗癌作用活性和铁死亡诱导。代表性化合物1和3的抗增殖活性分别比顺铂高140倍和90倍。我们的数据表明，贝特-铂（IV）前药在A549细胞中的积累远高于顺铂，随后细胞内脂质含量急剧下降，活性氧（ROS）水平升高，线粒体跨膜电位破坏，并显着抑制增殖。此外，我们的结果表明，贝特-Pt( IV )前药不仅诱导DNA损伤、细胞凋亡和细胞周期停滞，而且还导致脂质过氧化物、亚铁离子和丙二醛(MDA)的增加，以及谷胱甘肽，通过抑制 Xc-/GSH/GPX4 抗氧化防御轴系统和刺激铁轴来引发铁^死亡。我们的研究结果强调，将脂质代谢调节与铁死亡相结合来开发新型铂基抗癌药物可以产生优异的多作用抗癌活性，这可能代表一种有前途的癌症治疗方式。