Structural optimization and functional evaluation of cytisine for redox homeostasis regulation in lung cancer cells

• YU-C-ThioU-9 was identified as a potent antitumor lead compound from a novel library of cytisine-based derivatives. • It exerts its effect by disrupting redox homeostasis, leading to ROS accumulation, oxidative damage, and ultimately apoptosis in cancer cells. • YU-C-ThioU-9 exhibited robust anticancer efficacy in both in vitro and in vivo models. • The study establishes redox disruption as a viable and clinically actionable strategy for precision oncology. Targeting redox homeostasis represents a promising strategy to selectively eliminate cancer cells through oxidative stress-mediated apoptosis. However, developing specific molecular entities capable of effectively disrupting this balance remains a key challenge. This study aimed to construct a novel library of cytisine derivatives through rational drug design to discover lead compounds with potent redox-disrupting activity and validate their potential as precision therapy candidates for lung cancer. A focused library of 77 derivatives was designed and synthesized via rational modification of key pharmacophores in cytisine. The antitumor activity and mechanism of action of candidate compounds were evaluated using in vitro cellular models and in vivo animal models. Among these, YU-C-ThioU-9 emerged as a lead compound with potent antitumor activity. Mechanistic investigations revealed that YU-C-ThioU-9 disrupts intracellular redox balance, leading to a marked accumulation of reactive oxygen species (ROS) and consequent oxidative damage. This redox perturbation, marked by oxidative stress accumulation, ultimately induces apoptotic cell death in lung cancer cells. Importantly, YU-C-ThioU-9 exhibited robust anticancer efficacy in both in vitro and in vivo models. These findings establish redox disruption as a clinically actionable avenue for precision oncology and position YU-C-ThioU-9 as a lead cytisine-derived candidate for lung cancer therapy.