COMMENTARY Plasma nontransferrin bound iron–nontransferrin bound iron revisited: Implications for systemic iron overload and in iv iron supplementation Ioav Z. Cabantchik 1 | Chaim Hershko 2 1 Institute of Life Sciences, Faculty of Natural Sciences, Hebrew University of Jerusalem, Jerusalem, Israel 2 Institute of Medicine, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel Correspondence Ioav Z. Cabantchik. Alexander Silberman Institute of Life Sciences, Department of Biological Chemistry, Safra Campus at Givar Ram, Jerusalem 91904, Israel. Email: ioav.caban@mail.huji.ac.il Nontransferrin bound iron (NTBI) has been classically used to denote a potentially toxic component of plasma detected in systemic iron overload and implicated in end-organ iron accumulation and biological damage. A chelatable labile component of plasma NTBI has also served as target for novel therapeutics. However, as the term NTBI per se does not exclude nontoxic forms of iron that can be detected in plasma, its liberal use without additional pharmacological attributes might be misleading, especially in the clinical context, as for infusible iron supplements. In keeping with the historical and commonly used NTBI term, we propose here to use “labile/nonlabile” plasma NTBI to indicate the toxic potential of the iron species in question. Iron overload (IO) is a pathological condition caused by the accu- mulation of iron in excess of physiological needs, ultimately resulting in oxidative damage to vital functions. The early diagnosis of the most prevalent IO pathologies has classically relied on the two systemic iron plasma markers, ferritin, and transferrin saturation (TSAT). The end-organ accumulation of iron and ensuing damage were attributed to the opportunistic ingress of nontransferrin bound iron (NTBI) species from plasma to cells, via undefined membrane pathways. The early definition of NTBI in IO plasma (TSAT ≥ 100%) was of an iron species of relatively low molecular weight iron that is not associated with the physiological iron carrier transferrin, insofar as it was cap- tured by a chelator and filterable via dialysis. 1,2 The putative NTBI species was subsequently referred to as plasma catalytic iron, based on its propensity to generate reactive oxygen species (ROS), a prop- erty commonly implicated in peroxidative damage. 3 1 | NTBI-ORIGIN AND TERMINOLOGY Although NTBI per se implies generically all forms of iron not-bound to transferrin, its usage in biology and medicine (especially in hematology), has been confined to either chelatable or catalytic iron in internal biological fluids (reviewed in Brissot et al., 2012. doi: 0.1016/j.bbagen.2011.07.014 and Cabantchik, 2014. doi: 10.3389/ fphar.2014.00045).* ,4,5 As NTBI was detected in plasma of patients with IO (TSAT>70%), it was viewed as a marker of systemic IO but also inferred as source of impending tissue IO, namely as a potential source of unregulated tissue iron ingress and ensuing accumulation to toxic levels (see also review by Porter & Garbowski, 2014. doi: 10.1016/j.hoc.2014.04.003). 6 Although the suggested origin of tissue IO and peroxidative damage was identified with the fraction of plasma iron not associated with transferrin, the role of plasma NTBI in IO pathology was essentially deduced from the protective effect afforded by iron chelators with limited permeation to cells. The abil- ity of chelators to complex plasma NTBI, was subsequently used in the treatment of systemic IO to assess chelation efficacy by differ- ent chelation regimens. The generation of NTBI in human plasma reflects the failure of transferrin to capture all iron outpouring into circulation via the ferroportin export system. Transferrin's failure results primarily from a “local insufficiency” of apotransferrin (measurable as UIBC-unsaturated iron-binding capacity) due primar- ily to the lack of transferrin as in hereditary aceruloplasminemia, liver failure, or insufficient apotransferrin or when iron is under- utilized by the hematopoietic system (see also review by Coates, 2014. doi: 10.1016/j.freeradbiomed.2014.03.039). 7 As NTBI is gen- erally removed from circulation by the liver, its plasma levels reflect the dynamics of NTBI generation vis a vis its removal from plasma. Thus, NTBI builds up whenever production exceeds removal from circulation, as found in various types of IO of transfusional origin but also in nontransfusional overload that results from hyperabsorption of iron as in hereditary hemochromatosis or thalassemia intermedia, various forms of ineffective or suppressed erythropoiesis and espe- cially in atransferrinemia). Received: 30 August 2021 Revised: 6 October 2021 Accepted: 7 October 2021 DOI: 10.1002/ajh.26374 Am J Hematol. 2021;1–3. wileyonlinelibrary.com/journal/ajh © 2021 Wiley Periodicals LLC. 1