Iron metabolism dysregulation: a novel perspective on B-cell lymphomagenesis, drug resistance and targeted therapy

Iron is a trace element indispensable for fundamental cellular processes, whose metabolism is regulated homeostatically at both systemic and cellular levels. Crucial components of iron metabolism comprise: transferrin receptor 1 (TfR1)-mediated cellular iron uptake; non-transferrin-bound iron (NTBI) uptake under pathological conditions; intracellular iron storage accomplished through ferritin; and systemic regulation governed by hepcidin. In cancer, this delicate balance is frequently disrupted. Dysregulation of iron metabolism in B-cell lymphomas promotes tumor progression through several mechanisms. These include epigenetic reprogramming—exemplified by the activation of the iron-dependent histone demethylase KDM4A—and exacerbation of oxidative stress, which can foster genomic instability. The consequences of iron metabolism dysregulation are closely linked to ferroptosis, an iron-dependent form of regulated cell death characterized by lethal lipid peroxidation. In B-cell lymphomas, tumor cells often develop mechanisms to evade ferroptosis; for instance, by upregulating the HSPA5/GPX4 axis to suppress lipid peroxidation and enhance cell survival. Therapeutically, targeting iron metabolism pathways holds promise. Strategies include depleting intracellular iron pools using iron chelators and employing nanotechnology for the targeted delivery of iron-loaded nanoparticles or ferroptosis inducers to selectively trigger ferroptosis. These approaches underscore the potential of targeting iron metabolism for the treatment of B-cell lymphomas, offering novel avenues to improve therapeutic outcomes.