<p>Ferroptosis, a unique modality of regulated cell death, is intricately intertwined with lipid peroxidation, a process tightly regulated by lipid metabolism. Herein, a Pt(IV) prodrug, CB, <i>cis</i>,<i> cis</i>,<i> trans</i>-[Pt(NH₃)₂Cl₂(BEZ)(OH)] (BEZ = bezafibrate), previously designed by conjugating the clinical platinum drug cisplatin with the lipid-modulating agent bezafibrate, exhibited potent anticancer efficacy via a unique mechanism of action independent of peroxisome proliferator-activated receptor α (PPARα) activation. Oil Red O staining and ultra-high-performance liquid chromatography-mass spectrometry (UPLC-MS) analysis revealed that CB reduced the total lipid content and altered the free fatty acid (FFA) profile in A549 cells. This alteration led to a reduction in both saturated fatty acids (SFA) and monounsaturated fatty acids (MUFA), while concurrently enhancing the proportion of polyunsaturated fatty acids (PUFA) to MUFA ratio. This change in lipid composition enhances the susceptibility of the cell membrane to lipid peroxidation, thereby triggering the ferroptosis. The antiproliferative effect of CB was partially reversed by the ferroptosis inhibitor, ferrostatin-1, confirming the involvement of ferroptosis. Mechanistically, CB induces lipid peroxidation, disrupts iron homeostasis (elevated Fe²⁺), and impairs redox balance (decreased GSH and increased MDA). Western blot analysis revealed that CB inhibits the Xc⁻/GSH/GPX4 antioxidant system and modulates iron pathway proteins. This multifaceted mechanism, which combines lipid modulation, ferroptosis induction, and DNA damage, highlights the potential of targeting lipid metabolism in cancer therapy.</p> Graphical abstract <p>Pt(IV) prodrug, CB, a combination of cisplatin and bezafibrate, acts via a multifaceted anticancer mechanism including lipid-modulating, ferroptosis induction, apoptosis induction and DNA damage.</p>