手性在各种生物过程中发挥着不可或缺的作用，手性对映体与生物分子靶标之间的相互作用为精准药物开发提供了新的视角。虽然铁死亡作为逆转耐药性的新途径受到越来越多的关注，但通过手性编程设计精确的铁死亡靶向分子的工作仍然有限。在这项工作中，我们通过抑制铁死亡抑制蛋白-1（FSP1）设计并合成了一对手性依赖性铁死亡诱导Ir(iii)-苯基喹唑啉酮复合物（Δ-IrPPQ和Λ-IrPPQ），而这对IrPPQ复合物诱导极其不同的铁死亡效应以及对胰腺癌细胞的独特光动力疗法（PDT）反应。有趣的是，通过蛋白质组学分析和分子模拟，这种手性依赖性生物机制揭示了Λ-IrPPQ对金属硫蛋白-1（MT1）的特异性结合和抑制使癌细胞对铁死亡敏感，诱导活性氧簇、脂质过氧化、谷胱甘肽的爆发。 FSP1 的耗尽和失活。相比之下，Δ-IrPPQ 诱导轻度铁死亡细胞死亡。通过简单的手性拆分，获得的Λ-IrPPQ实现了对胰腺癌细胞铁死亡的精确调控。这项工作为未来胰腺癌治疗的手性铁死亡诱导金属药物的设计提供了新的见解。该期刊版权所有©英国皇家化学学会。

Chirality plays an indispensable role in various biological processes, and interactions between chiral enantiomers and biomolecular targets provide new perspectives in precision drug development. While ferroptosis has received increasing attention as a novel pathway to reverse drug resistance, work on the design of precise ferroptosis-targeting molecules through chiral programming was limited. In this work, we designed and synthesized a pair of chirality-dependent ferroptosis-inducing Ir(iii)-phenylquinazolinone complexes (Δ-IrPPQ and Λ-IrPPQ) by inhibiting ferroptosis suppressor protein-1 (FSP1), while the pair of IrPPQ complexes induced extremely different ferroptosis effects as well as distinct photodynamic therapy (PDT) responses toward pancreatic cancer cells. Interestingly, this chirality-dependent biological mechanism through proteomic analysis and molecular simulation revealed that the specific binding and inhibition of metallothionein-1 (MT1) by Λ-IrPPQ sensitized cancer cells to ferroptosis, inducing a burst of reactive oxygen species, lipid peroxidation, glutathione depletion, and inactivation of FSP1. While in comparison, Δ-IrPPQ induced mild ferroptotic cell death. Through simple chiral resolution, the obtained Λ-IrPPQ achieved precise regulation of ferroptosis in pancreatic cancer cells. This work provides new insights into the design of chiral ferroptosis-inducing metallodrugs for future pancreatic cancer therapy.This journal is © The Royal Society of Chemistry.