Novel Bioactive Peptides Inducing ROS ‐Mediated Apoptosis in Colorectal Cancer Cells

ABSTRACT Cationic anticancer peptides (ACPs) have gained attention, partly due to their ability to interact with negatively charged cancer cell membranes. In this study, Myxoma Virus (MV) peptide analogs were rationally designed using the Resonant Recognition Model (RRM) to assess the impact of charge and conformational variations on anticancer activity against colorectal cancer (HCT‐8) cells. The synthesized peptides exhibited potent, dose‐dependent cytotoxicity, with IC 50 values of 950, 2000, 1100, and 1300 ng/mL, indicating variable efficacy among analogs. Microscopic and fluorescence analyses revealed classical apoptotic features such as chromatin condensation, membrane blebbing, and apoptotic body formation. Annexin V assays confirmed apoptosis induction, while elevated reactive oxygen species (ROS) generation indicated ROS‐mediated apoptosis as the dominant mechanism. Despite structural modifications, all peptides retained significant anticancer potential, demonstrating structural resilience and mechanistic consistency. The study highlights the therapeutic promise of MV‐derived peptides as selective, ROS‐inducing agents against colorectal cancer.