Duca Lorena, Di Pierro Elena, Scaramellini Natalia, Granata Francesca, Graziadei Giovanna
SC Medicina ad Indirizzo Metabolico, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.
Dipartimento di Scienze Cliniche e di Comunità, Dipartimento di Eccellenza 2023-2027, Università degli Studi di Milano, 20122 Milan, Italy.
Int J Mol Sci. 2025 Jul 3;26(13):6433. doi: 10.3390/ijms26136433.
Plasma non-transferrin-bound iron (NTBI) comprises multiple subspecies, classified by their composition, chemical reactivity, and susceptibility to chelation. The redox-active and chelatable fraction of NTBI is referred to as labile plasma iron (LPI). The pathophysiological significance of NTBI and LPI lies in their ability to enter cells via alternative transport pathways that are not regulated by the transferrin receptor system or by cellular iron levels. Several mechanisms have been proposed for their cellular entry, including the hijacking of divalent metal transporters and passive diffusion. This unregulated uptake can lead to iron accumulation in vulnerable tissues such as the liver and the heart. NTBI and LPI bypassing normal cellular control mechanisms can rapidly exceed the cell's capacity to safely store excess iron, leading to toxicity. Both NTBI and LPI contribute to oxidative stress by participating in free-radical-generating reactions. However, LPI concentration in the bloodstream may be differentially affected by the mode and extent of iron overload, the presence of residual serum iron-binding activity, and the antioxidant capacity of individual sera. In summary, both NTBI and LPI contribute to iron-mediated toxicity but differ in terms of reactivity, availability, and pathogenic potential depending on the pathophysiological conditions that influence the degree of toxicity.
血浆非转铁蛋白结合铁（NTBI）由多个亚类组成，根据其组成、化学反应性和对螯合作用的敏感性进行分类。NTBI的氧化还原活性和可螯合部分被称为不稳定血浆铁（LPI）。NTBI和LPI的病理生理意义在于它们能够通过不受转铁蛋白受体系统或细胞铁水平调节的替代转运途径进入细胞。关于它们进入细胞的机制，已经提出了几种，包括劫持二价金属转运体和被动扩散。这种不受调节的摄取会导致铁在肝脏和心脏等易损组织中积累。NTBI和LPI绕过正常的细胞控制机制，会迅速超过细胞安全储存过量铁的能力，从而导致毒性。NTBI和LPI都通过参与产生自由基的反应而导致氧化应激。然而，血液中LPI的浓度可能会受到铁过载的方式和程度、残余血清铁结合活性的存在以及个体血清抗氧化能力的不同影响。总之，NTBI和LPI都导致铁介导的毒性，但根据影响毒性程度的病理生理条件，它们在反应性、可用性和致病潜力方面存在差异。
