Targeting ferritinophagy to regulate ferroptosis: small molecule strategies and therapeutic opportunities

Iron homeostasis is maintained through a dynamic equilibrium between iron storage and mobilization, in which ferritin serves as the central intracellular iron reservoir. Ferritinophagy, a specialized subtype of selective autophagy mediated by the cargo receptor Nuclear Receptor Coactivator 4 (NCOA4), is responsible for the lysosomal degradation of ferritin and the subsequent release of free iron into the labile iron pool. By controlling the flux of intracellular iron, ferritinophagy occupies a pivotal position upstream regulator of ferroptosis and represents a critical determinant of cellular ferroptotic sensitivity. Recent advances in structural biology have elucidated the molecular architecture governing ferritinophagy, including the NCOA4-FTH1 binding interface, the iron-sulfur cluster-dependent sensing mechanism that couples intracellular iron levels to NCOA4 stability, and the HERC2-mediated ubiquitin-proteasome degradation circuit. These mechanistic insights have revealed multiple druggable nodes within the ferritinophagy pathway, stimulating growing interest in small-molecule intervention strategies. Herein, this narrative review aims to systematically dissect the ferritinophagy-ferroptosis regulatory network, categorize diverse small-molecule modulators, grade pre-clinical evidence for candidate agents, and highlight major translational bottlenecks for future therapeutic development. This review systematically summarizes the molecular mechanisms of NCOA4-mediated ferritinophagy and its regulatory crosstalk with ferroptosis, and comprehensively evaluates small-molecule modulators targeting this pathway. These agents fall into two principal conceptual strategies: ferritinophagy activators that promote iron release to drive ferroptotic tumor cell death, and ferritinophagy inhibitors that restrict iron mobilization to confer cytoprotection in normal tissues. Most candidate agents described remain pre-clinical investigational tools or repurposed compounds without dedicated clinical validation for ferritinophagy-related endpoints. Only a small subset of molecules (e.g., iron chelators deferiprone and deferoxamine) are clinically approved for unrelated primary indications. We discuss pre-clinical therapeutic potential of this axis across cancer, neurodegeneration, and organ injury, while explicitly highlighting major pharmacokinetic, specificity, and translational bottlenecks that must be overcome prior to clinical deployment of ferritinophagy-directed therapies. This review systematically sorts out the multi-layer regulatory mechanisms linking ferritin turnover and ferroptosis. It categorizes small molecules regulating ferritin breakdown and summarizes their dual therapeutic values in diverse diseases. The work outlines major translational obstacles limiting clinical application of ferritin-targeted intervention strategies. It proposes integrated research approaches to advance precise iron metabolism-targeted disease treatments.