Research advances in single-molecule multi-target strategies targeting ferroptosis for colorectal cancer treatment.

Abstract

Colorectal cancer (CRC) is a highly prevalent malignancy worldwide, with its incidence and mortality continuing to rise, and with an emerging trend toward younger-onset disease. The efficacy of current treatment modalities, including surgery, chemotherapy, targeted therapy, and immunotherapy, is often limited by the development of drug resistance. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, is governed by a sophisticated regulatory network comprising core pathways and bypass systems in CRC, offering numerous potential targets for therapeutic intervention. The single-molecule multi-target strategy employs a single compound to simultaneously act upon multiple key nodes within this network, circumventing the resistance commonly associated with single-target agents while avoiding the pharmacokinetic interactions and additive toxicities of drug combinations. This review systematically delineates the key pathways and core targets of ferroptosis in CRC and summarizes recent progress across three classes of single-molecule multi-target compounds: natural products, synthetic small molecules, and "one-drug multi-modal death" inducers. We further propose a drug development and design framework integrating structural optimization, target integration, and delivery efficiency. Finally, we discuss current challenges and future directions, aiming to provide a theoretical foundation for developing novel CRC treatment strategies.