Ferroptosis Pharmacology: Molecular Mechanisms, Therapeutic Targets and Emerging Strategies for Precision Medicine

Abstract

Ferroptosis is a distinctive form of regulated cell death characterized by iron-dependent accumulation of oxidized polyunsaturated fatty acid-containing phospholipids, disruption of cellular redox homeostasis, and irreversible membrane injury. Unlike apoptosis, necroptosis, and pyroptosis, ferroptosis is principally governed by the interplay between iron metabolism, lipid remodeling, reactive oxygen species generation, and endogenous antioxidant defense systems. The glutathione-dependent glutathione peroxidase 4 (GPX4) pathway represents a central ferroptosis-suppressive axis, whereas ferroptosis suppressor protein 1 (FSP1), dihydroorotate dehydrogenase (DHODH), and the GTP cyclohydrolase 1 (GCH1)-tetrahydrobiopterin (BH4) pathway constitute additional protective mechanisms. Pharmacological induction of ferroptosis has attracted substantial interest in oncology because malignant cells frequently exhibit increased iron requirements, altered lipid metabolism, elevated oxidative stress, and dependence on specific antioxidant systems. Conversely, pharmacological inhibition of ferroptosis may be beneficial in pathological conditions in which excessive lipid peroxidation contributes to tissue injury, including ischemia-reperfusion injury, cardiovascular disorders, neurodegenerative diseases, and organ dysfunction. Several experimental ferroptosis inducers act through inhibition of system xc−, depletion of glutathione, direct inhibition or degradation of GPX4, perturbation of iron homeostasis, or enhancement of lipid peroxidation. Ferroptosis-targeting strategies are also being investigated in combination with chemotherapy, radiotherapy, targeted therapy, and immunotherapy. Nevertheless, translation into clinical practice remains constrained by inadequate selectivity, pharmacokinetic limitations, tissue toxicity, biological heterogeneity, and the absence of universally accepted pharmacodynamic biomarkers. This review summarizes the pharmacological basis of ferroptosis, its molecular regulatory networks, major ferroptosis-inducing and ferroptosis-inhibiting strategies, therapeutic applications, current challenges, and future directions for the development of ferroptosis-directed pharmacotherapies.