Iron: The Gatekeeper of Cellular Vitality and Ferroptosis—Unraveling Its Intricate Journey Through Human Physiology
Iron, a pivotal biometal, commands a unique position at the crossroads of life and cell death, wielding profound influence over processes ranging from oxygen transport to the enigmatic ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation. Navigating the labyrinthine pathways of iron metabolism reveals a sophisticated orchestration of absorption, transport, storage, and regulation, each step meticulously calibrated to preserve systemic balance. The human body’s iron economy, remarkable in its scale, is dominated by recycling mechanisms that extract over 90% of the iron needed for erythropoiesis—approximately two to three quadrillion atoms per second in an adult—underscoring the metal’s non-negotiable role in sustaining life.
Central to this finely tuned system is the intestine, where dietary iron, arriving in heme and non-heme forms, undergoes precise biochemical transformations to facilitate absorption. Enterocytes employ specialized proteins like haem carrier protein 1 (HCP1) to internalize heme-bound iron directly. Meanwhile, the more abundant non-heme iron, typically in its ferric (Fe³⁺) state, is reduced by the duodenal cytochrome b (Dcytb) enzyme at the apical membrane, converting it to the ferrous (Fe²⁺) form amenable to the divalent metal transporter 1 (DMT1). This reduction is a critical gateway that enables iron’s entry into the enterocyte cytoplasm for further systemic distribution.
The iron export orchestrated by the ubiquitous ferroportin (FPN), the sole known mammalian iron exporter, marks a pivotal juncture in systemic iron homeostasis. Ferroxidases such as hephaestin (HEPH), intimately linked with intestinal epithelia, along with ceruloplasmin (CP) synthesized by hepatocytes, mediate the oxidation of Fe²⁺ back to Fe³⁺, facilitating its binding to transferrin (Tf) for safe transit through the plasma to developing erythroid precursors and other iron-dependent tissues. This elegant coupling ensures that iron is shuttled efficiently, minimizing its free radical-generating potential.
At the cellular frontier, transferrin receptors (TfRs) serve as gatekeepers, enabling the Tf-bound Fe³⁺ complex to be internalized by receptor-mediated endocytosis. The acidification of endosomes prompts the dissociation of Fe³⁺ from transferrin, followed by its reduction to Fe²⁺ by metalloreductases like STEAP3. This ferrous iron traverses the endosomal membrane via DMT1 or ZIP transporters to enrich the cytosolic labile iron pool (LIP), a dynamic reservoir instrumental for metabolic demands and mitochondrial function. Notably, transferrin receptor 2 (TfR2), with a mitochondrial targeting sequence, facilitates direct iron trafficking to mitochondria where it fuels heme biosynthesis and the assembly of critical iron-sulfur clusters.
Intracellular iron levels are deftly buffered by ferritin, a macromolecular cage-like protein complex capable of sequestering up to 4,500 iron atoms. Comprised of heavy (H) and light (L) subunits whose proportions vary with tissue specificity and developmental stage, ferritin embodies a crucial cytoplasmic iron repository, mitigating oxidative damage elicited by free iron via its ferroxidase activity. Beyond its cytosolic dominance, ferritin is also resident in mitochondria and the nucleus, reflecting iron’s multifaceted cellular roles.
Paralleling Tf/TfR’s role in iron uptake, ferritin itself engages cell surface receptors such as TIM-2, Scara5, and intriguingly, transferrin receptor 1 (TfR1), enabling intercellular ferritin-iron delivery and emphasizing the interplay between iron storage and mobilization pathways. This duality of ferritin as both an iron storehouse and a transport mediator challenges established paradigms and opens avenues for understanding iron’s spatial and temporal regulation.
Control of ferroportin abundance and activity is paramount, given its gatekeeper role in cellular iron release. Hepcidin, a liver-derived peptide hormone, adjusts ferroportin presence at the plasma membrane in response to systemic iron levels. Elevated iron elicits hepcidin synthesis, which binds ferroportin, inducing its internalization and degradation, effectively throttling iron egress from enterocytes and macrophages. Conversely, hepcidin suppression under low iron states liberates ferroportin, enhancing systemic iron availability. High-resolution structural studies have elucidated the molecular choreography whereby hepcidin occludes ferroportin’s iron passage in an iron-binding dependent manner, underscoring the precision of this regulatory switch.
Intriguingly, ferroportin also manifests dual functionality, capable of transporting calcium ions via a dedicated binding site distinct from its iron export domain. Calcium transport modulation by ferroportin introduces a layer of crosstalk between iron metabolism and calcium signaling, suggesting a sophisticated interdependency that could influence cellular homeostasis beyond iron alone.
The therapeutic landscape is witnessing the emergence of ferroportin-targeted interventions like vamifeport (VIT-2763), an oral inhibitor designed to mimic hepcidin’s binding site, competing for ferroportin occupancy and modulating iron export. Being evaluated clinically in hemoglobinopathy disorders such as β-thalassemia and sickle cell disease, such approaches exemplify the translational potential arising from deep mechanistic insights.
Cellular iron handling is further refined by poly(RC)-binding proteins (PCBPs), which chaperone iron delivery to ferritin for storage while engaging heme oxygenase 1 (HO1) for heme degradation. PCBPs also orchestrate the function of iron-dependent enzymes implicated in lipid peroxidation pathways, mitochondrial metabolism, and post-translational modifications, linking iron metabolism to broader biochemical networks influencing cell fate decisions.
At a pathophysiological level, perturbations in iron homeostasis implicate Tf and TfRs in a spectrum of diseases from anemia to neurodegeneration. Dysregulated ferroportin expression can exacerbate tissue iron overload or deficiency, with consequences ranging from hepatic fibrosis via macrophage polarization shifts to Alzheimer’s disease progression through ferroptotic neuronal death. The iron regulatory protein (IRP)/iron-response element (IRE) system fine-tunes TfR expression, ensuring adaptive responses to cellular iron fluctuations; this regulatory axis is modulated further by hypoxia-inducible factors (HIFs) and microRNAs, highlighting multilayered control at transcriptional and post-transcriptional tiers.
The iron narrative intertwines with mitochondrial function, where TfR2 facilitates directed iron trafficking to satisfy demand for heme and iron-sulfur clusters integral to respiratory chain enzyme assemblies. Lysosomal dynamics, involving trafficking of TfR2-containing vesicles toward mitochondria, underscore specialized inter-organelle communication essential for iron’s bioenergetic roles.
Ferroptosis, increasingly recognized as an iron-dependent form of regulated cell death characterized by lethal lipid peroxidation, places iron metabolism at its epicenter. The dynamic storage and mobilization of iron, orchestrated by ferritinophagy mediated via NCOA4 and the labile iron pool’s redox interactions, create a delicate balance between survival and death signaling. Understanding these molecular intricacies offers promising directions for therapeutic modulation in cancer, neurodegeneration, and inflammatory diseases where ferroptosis operates.
Collectively, the body’s iron transport network—from dietary absorption and recycling via macrophages to intracellular trafficking and controlled release—constitutes a masterclass in biological precision. The integration of transport proteins, storage complexes, regulatory hormones, and chaperones forms a robust yet adaptable framework essential for life. Dissecting and leveraging this complexity unlocks potentially transformative strategies in medicine, with ferroportin standing out as a linchpin target in controlling iron flux and ferroptosis susceptibility.
As research continues to decode the crosstalk between iron metabolism, redox biology, and cellular fate, we are poised on the cusp of innovations that will redefine therapeutic interventions for a plethora of iron-linked diseases. Iron’s journey, from diet to cellular destiny, remains one of the most compelling stories in human biology, with its redox paradoxes and regulatory nuances offering endless inquiry into the essence of cellular vitality and demise.
Subject of Research: Iron metabolism and its regulation in systemic and cellular contexts, with emphasis on iron absorption, transport, storage, and its role in ferroptosis.
Article Title: Redox mechanism of glycerophospholipids and relevant targeted therapy in ferroptosis.
Article References:
Chang, S., Zhang, M., Liu, C. et al. Redox mechanism of glycerophospholipids and relevant targeted therapy in ferroptosis. Cell Death Discov. 11, 358 (2025). https://doi.org/10.1038/s41420-025-02654-y
Image Credits: AI Generated
