Ferritinophagy as a Double-Edged Sword in Cancer: Novel Insights into Therapeutic Targeting of Iron-Driven Ferroptosis.

Iron metabolism and its regulation through ferritinophagy have emerged as critical yet under-explored determinants of cancer cell fate, uniquely bridging essential biological processes such as DNA synthesis, oxidative metabolism and cellular respiration with iron-dependent cell death pathways like ferroptosis. This review presents a novel and integrative analysis of ferritinophagy mediated predominantly by nuclear receptor coactivator 4 (NCOA4) as a pivotal regulator of iron homeostasis, exhibiting highly context-dependent roles in cancer progression, survival and therapeutic resistance. We synthesize recent mechanistic advances to show how ferritinophagy can either support tumor growth by satisfying iron-driven metabolic demands or trigger ferroptosis-mediated tumor suppression; a duality seldom examined in prior literature. We further examine the interplay between ferritinophagy and antioxidant defense systems, particularly the NRF2 signaling network, and how this balance affects treatment outcomes. Importantly, we consolidate emerging therapeutic strategies that exploit ferritinophagy modulation namely targeted small molecules, bioactive natural compounds, nanotechnology-facilitated delivery systems, and RNA-based interventions thereby positioning ferritinophagy as a promising target in precision oncology. We then critically discuss the major translational challenges: tumor heterogeneity in iron-metabolism phenotypes, the risk of off-target toxicity disrupting systemic iron homeostasis, the dearth of reliable biomarkers to monitor ferritinophagy flux and delivery/pharmacokinetic limitations in reaching specific tumor niches. Our integrative approach offers fresh perspectives on how ferritinophagy interfaces with cancer-relevant pathways across diverse tumor types, emphasizing its potential both as a vulnerability to exploit and a mechanism of resistance to overcome. This work thus lays a foundation for future research into ferritinophagy-centred interventions that may enhance cancer treatment efficacy.