Lipoic acid-conjugated chalcones exert antitumor activity via ROS elevation and ferroptosis.

Abstract

Overcoming drug resistance and minimizing off-target toxicity remain major challenges in cancer therapy. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a promising therapeutic target. Natural chalcones exhibit antitumor properties linked to oxidative stress induction, yet efficacy and selectivity are limited. To achieve this, we designed and synthesized a series of novel α-lipoic acid (LA)-conjugated chalcone derivatives with the aim of disrupting redox and iron homeostasis to induce ferroptosis in cancer cells. Here, we report that these conjugates elevate reactive oxygen species (ROS) levels most prominently in T24 bladder cancer cells, compared to other tested cell lines, leading to potent growth inhibition and suppressed migration. Mechanistically, RNA-seq and functional assays reveal that the lead compound CA-LA triggers ferroptosis by dysregulating cellular iron and glutathione metabolism. Our work presents a rational design strategy for redox-directed antitumor agents and identifies LA-chalcone hybrids as promising candidates for selective bladder cancer therapy via ferroptosis induction.