Monitoring of Propiolamide-Mediated Molecular Crosstalk between Ferroptosis and Apoptosis by Raman Spectroscopy

Inducing programmed cell death is an efficient strategy for cancer treatments, and a deep understanding of the molecular mechanisms underlying cell death pathways is of significance for the rational design of anticancer drugs. Herein, propiolamide-mediated crosstalk between ferroptosis and apoptosis is investigated. In situ monitoring of reactive oxygen species (ROS) formation and the structural changes of propiolamide compounds is achieved by Raman spectroscopy. The molecular mechanisms of propiolamides in inducing monooxygenase-mediated ROS generation and inhibiting GPX4 activities are revealed. Furthermore, the pro-ferroptotic and pro-apoptotic roles of the propiolamides containing terminal alkynes are verified. This study provides an in situ and label-free strategy for monitoring enzyme–drug interactions and their dynamics. It is a first attempt to study the structural basis of molecular crosstalk through two important enzymes in cell death. This study paves the way for designing novel drugs that are capable of triggering a synergistic contribution of multiple cell death forms to anticancer efficacy.