Ferroptosis‐modulating small molecules for targeting drug‐resistant cancer: Challenges and opportunities in manipulating redox signaling

Ferroptosis is an iron‐dependent cell death program that is characterized by excessive lipid peroxidation. Triggering ferroptosis has been proposed as a promising strategy to fight cancer and overcome drug resistance in antitumor therapy. Understanding the molecular interactions and structural features of ferroptosis‐inducing compounds might therefore open the door to efficient pharmacological strategies against aggressive, metastatic, and therapy‐resistant cancer. We here summarize the molecular mechanisms and structural requirements of ferroptosis‐inducing small molecules that target central players in ferroptosis. Focus is placed on (i) glutathione peroxidase (GPX) 4, the only GPX isoenzyme that detoxifies complex membrane‐bound lipid hydroperoxides, (ii) the cystine/glutamate antiporter system Xc− that is central for glutathione regeneration, (iii) the redox‐protective transcription factor nuclear factor erythroid 2‐related factor (NRF2), and (iv) GPX4 repression in combination with induced heme degradation via heme oxygenase‐1. We deduce common features for efficient ferroptotic activity and highlight challenges in drug development. Moreover, we critically discuss the potential of natural products as ferroptosis‐inducing lead structures and provide a comprehensive overview of structurally diverse biogenic and bioinspired small molecules that trigger ferroptosis via iron oxidation, inhibition of the thioredoxin/thioredoxin reductase system or less defined modes of action.