At the cellular level, the master regulators are the iron regulatory proteins, IRP1 and IRP2, which operate through a remarkably elegant post-transcriptional circuit. These proteins bind to iron-responsive elements, or IREs, which are hairpin structures folded into the untranslated regions of specific messenger RNAs. When cellular iron is scarce, IRPs clamp onto IREs located near the start of transcripts, physically blocking the ribosome from translating them. This is how the cell silences production of ferritin, the iron-storage protein, and of ferroportin, the sole known iron exporter, ensuring that whatever iron is present stays inside the cell rather than being locked away or shipped out. Simultaneously, the same IRPs bind IREs in the 3-prime untranslated region of the transcript encoding transferrin receptor 1, the protein that imports iron-bound transferrin from the blood. There, binding stabilizes the mRNA against degradation, boosting receptor production and iron uptake. The result is a two-pronged switch: low iron turns on import and turns off export and storage, while iron abundance flips the entire program in the opposite direction.

The sensing mechanism itself is a story of molecular transformation. IRP1 is, in fact, a dual-function protein: when iron is plentiful, it assembles a 4Fe-4S iron-sulfur cluster into its active site and converts into cytosolic aconitase, an enzymatic relic of its evolutionary origin, losing its RNA-binding capacity in the process. When iron levels fall, the cluster disassembles and the protein reverts to its RNA-binding form. IRP2, which lacks the aconitase function, is regulated instead through iron-dependent degradation: in iron-replete conditions it is ubiquitinated following iron-dependent oxidation and destroyed by the proteasome. Two sensors, two mechanisms, one coherent output. This system also intersects with oxygen sensing, because hypoxia modulates IRP activity, linking iron availability to the oxygen-dependent metabolic state of the cell, a connection reflected in the review’s emphasis on hypoxia as a keyword of the field.

Cellular control, however, is only half the story. The body must decide globally how much iron to absorb from the diet, how much to release from storage, and how much to allocate to the single largest iron consumer: the erythron, the billions of developing red blood cells that require roughly twenty to twenty-five milligrams of iron daily in an adult human. Humans have no regulated route of iron excretion, so systemic balance is achieved almost entirely by controlling absorption at the duodenal enterocyte and release from iron-recycling macrophages. The linchpin of this control is hepcidin, a 25-amino-acid peptide hormone produced by the liver. Hepcidin binds to ferroportin on the surface of enterocytes, macrophages, and hepatocytes, triggering its internalization and degradation. With ferroportin removed, iron can neither leave the gut into the blood nor exit storage sites, and plasma iron falls. In effect, hepcidin is the body’s iron gatekeeper, and its concentration in plasma determines the flow of iron through the entire economy of the organism.

What makes hepcidin fascinating to researchers is the sophistication of its upstream wiring. The central signaling axis runs through the bone morphogenetic protein pathway: BMP6, produced in response to iron loading of liver sinusoidal endothelial cells, signals through SMAD transcription factors to switch on the HAMP gene encoding hepcidin. This pathway is tuned by a cast of accessory proteins. Hemojuvelin, encoded by HJV, acts as a co-receptor that amplifies BMP-SMAD signaling; mutations in HJV cause the most severe form of hereditary hemochromatosis, juvenile type, precisely because hepcidin production collapses. The transmembrane protease TMPRSS6, also known as matriptase-2, cleaves hemojuvelin from the cell surface, dampening the signal; loss-of-function mutations in TMPRSS6 produce iron-refractory iron deficiency anemia, a condition in which hepcidin remains inappropriately high and dietary iron cannot be absorbed. The review highlights FKBP12 as another layer of this circuit, a cytosolic protein that restrains BMP receptor signaling and thereby modulates hepcidin output, illustrating how finely the pathway is calibrated.

On top of the iron-sensing machinery sits a second regulatory layer that reads the body’s demand for iron. Transferrin receptor 2, a hepatocyte protein homologous to TFR1 but unable to bind IREs, senses the degree of transferrin saturation in plasma and transmits that information into the hepcidin pathway, working with the hemochromatosis protein HFE. Meanwhile, when red blood cell production accelerates, for example after hemorrhage, at altitude, or in response to anemia, erythroid cells in the bone marrow secrete erythroferrone, a hormone that suppresses hepcidin production, opening the ferroportin gates so that iron reserves can flow to the marrow. Inflammation adds yet another input: the cytokine interleukin-6 drives hepcidin up through the JAK-STAT pathway, sequestering iron in macrophages and hepatocytes and contributing to the anemia of chronic disease. The review’s central argument is that hepcidin regulation is not a single linear pathway but a dynamic integration hub, layering metabolic, stress, and environmental cues onto the core iron signal.

When these circuits fail, the clinical consequences are the disorders that have shaped human medicine for centuries. In hereditary hemochromatosis, mutations in HFE, TFR2, HJV, or hepcidin itself leave hepcidin inappropriately low relative to iron stores. Ferroportin stays active, dietary iron is absorbed relentlessly, and over decades the metal accumulates in the liver, pancreas, heart, and joints, causing cirrhosis, diabetes, cardiomyopathy, and arthritis if untreated. The disease illustrates the asymmetry of the system: because there is no excretory route, a small deficit in hepcidin translates into a lifelong positive iron balance. Conversely, when hepcidin is chronically elevated, as in inflammatory states or TMPRSS6 mutations, iron is locked away from the plasma and patients develop anemia that does not respond to oral iron supplementation, because the absorptive gate itself is closed.

Iron deficiency, the most common nutritional disorder worldwide, and iron overload thus represent opposite failures of the same regulatory logic, and understanding the circuits opens therapeutic doors. Drugs that stimulate the BMP-SMAD pathway or inhibit TMPRSS6 could raise hepcidin in beta-thalassemia and other iron-loading anemias, where suppressed hepcidin causes secondary overload even without transfusions. Conversely, hepcidin antagonists, including anti-hepcidin antibodies and BMP pathway inhibitors, could lower the hormone in anemia of inflammation, releasing iron trapped in macrophages. The review also points to emerging functions of iron-regulatory proteins that extend beyond their established roles, suggesting that IRPs and hepcidin pathway components participate in processes such as epigenetic regulation and stress responses, hinting that the iron system’s influence on physiology may be broader than the classical picture suggests.

What emerges from the synthesis is a picture of biological control at its most refined: a two-tier architecture in which every cell runs its own iron budget through post-transcriptional sensing, while a central hormonal circuit integrates stores, circulating iron, erythropoietic demand, inflammation, and hypoxia into a single systemic signal. The two tiers talk to each other, since ferroportin is both the target of hepcidin and an IRP-regulated transcript, creating feedback loops that span from the ribosome to the whole organism. For a field that began with the discovery of ferritin more than ninety years ago, the pace of discovery remains striking, and the Italian team’s comprehensive map arrives at a moment when hepcidin-targeted therapies are entering clinical development. Iron built the modern world of steel and oxygen, and inside our bodies, an equally engineered system of sensors, gates, and hormones keeps it in perfect, life-sustaining check.

Subject of Research: Molecular mechanisms of cellular and systemic iron homeostasis

Article Title: Circuits that guarantee iron homeostasis: from cellular sensing to systemic control

Article References: Silvestri, L., Pettinato, M., Carleo, R., Furiosi, V., Nai, A., & Pagani, A. (2026). Circuits that guarantee iron homeostasis: from cellular sensing to systemic control. Cellular and Molecular Life Sciences. https://doi.org/10.1007/s00018-026-06422-8

Image Credits: AI Generated

DOI: 10.1007/s00018-026-06422-8

Keywords: iron homeostasis, hepcidin, ferroportin, IRE-IRP system, transferrin receptor, BMP-SMAD pathway, TMPRSS6, hemochromatosis, iron deficiency, erythroferrone, hypoxia, gene regulation

MASLD is characterized by excess fat in liver cells in association with metabolic risk factors such as obesity, insulin resistance or type 2 diabetes. It can progress from relatively simple steatosis to metabolic dysfunction-associated steatohepatitis, fibrosis, cirrhosis and liver cancer. The disease is usually discussed in relation to diet, body weight, glucose regulation and inherited susceptibility, but environmental exposures may modify these processes. Bisphenols are endocrine-disrupting chemicals used in plastics, food and beverage packaging, thermal paper and other materials. BPA is the best-known member of the group, while bisphenol F and bisphenol S are among the substitutes increasingly used in products marketed as BPA-free. Biomonitoring studies have detected BPA and its analogues in human urine and blood, indicating widespread exposure. In the United States, estimates based on earlier national survey data placed median daily BPA intake at roughly 30 to 70 nanograms per kilogram of body weight. Exposure patterns are changing: restrictions have reduced BPA in some regions, while use of replacement compounds such as BPS and BPF has increased. The review argues that chemical substitution does not automatically remove biological concerns, because structurally related compounds can interact with hormone-sensitive pathways.

Iron is essential for oxygen transport, mitochondrial energy production and many enzyme reactions, but both too little and too much can damage the liver. The hormone hepcidin acts as the principal systemic regulator. Produced mainly by the liver, hepcidin binds to the iron-export protein ferroportin and causes it to be internalized and degraded. This reduces iron release from intestinal cells, macrophages and storage cells into the bloodstream. The review describes how iron deficiency can impair mitochondrial electron transport and fatty-acid oxidation, causing reactive oxygen species to rise while fat accumulates inside liver cells. Deficiency also reduces the activity of iron-dependent antioxidant systems and can stabilize hypoxia-inducible factors, or HIF proteins. HIF-1α and HIF-2α then alter gene programs controlling glucose and lipid metabolism. In particular, HIF-2α may increase expression of lipogenic genes such as SCD-1, FASN and ACC while suppressing PPARα and CPT1A, key regulators of fatty-acid breakdown. These changes can promote the buildup of triglycerides, diacylglycerol, ceramides and other lipids that interfere with insulin signaling and fuel inflammation.

Iron excess creates a different but equally damaging route to liver injury. Ferrous iron can drive the Fenton reaction, generating highly reactive hydroxyl radicals that attack proteins, membranes and mitochondrial structures. The resulting lipid peroxidation produces compounds such as malondialdehyde and 4-hydroxynonenal, which can further inhibit enzymes required for fatty-acid oxidation. Oxidative stress also activates inflammatory pathways including NF-κB, MAPK and JNK, while weakening PPARα activity and depleting glutathione, a major cellular antioxidant. If glutathione peroxidase 4, or GPX4, is impaired, lipid peroxides can accumulate to levels that trigger ferroptosis, a form of regulated cell death driven by iron-dependent membrane damage. Dying hepatocytes can activate Kupffer cells, the liver’s resident macrophages, which release inflammatory and fibrogenic signals such as tumor necrosis factor alpha and transforming growth factor beta. Those signals stimulate hepatic stellate cells, the principal producers of scar tissue in the injured liver. The review therefore portrays iron overload not as a passive marker of MASLD, but as a potential amplifier of steatosis, hepatocyte death and fibrosis.

Bisphenols may connect these two iron-related states through hormone receptors and redox signaling. Evidence summarized in the review points particularly to the G protein-coupled estrogen receptor, or GPER, as a candidate mediator of BPA-induced liver toxicity. Activation of GPER may stimulate an EGFR–PI3K–AKT–mTORC1 signaling cascade, suppressing NRF2-dependent antioxidant defenses and reducing glutathione synthesis. At the same time, bisphenols may increase reactive oxygen species by disturbing mitochondria and activating NADPH oxidase. Loss of glutathione can inactivate GPX4, allowing lipid peroxides to accumulate. The review proposes that this oxidative environment may then increase expression of iron-import proteins such as transferrin receptor 1 and divalent metal transporter 1, drawing more iron into hepatocytes. The additional iron would intensify Fenton chemistry and create a self-reinforcing cycle of iron accumulation, oxidative injury and impaired lipid metabolism. Animal and cell studies support parts of this model, including links between BPA or BPS exposure, altered iron-regulatory genes, ferroptosis and hepatic fat accumulation. However, the authors stress that the complete sequence has not been demonstrated in exposed human livers.

Hepcidin may help explain the review’s proposed paradox of hepatic iron overload alongside systemic iron deficiency. Bisphenols could affect hepcidin differently in different tissues or at different stages of exposure. In the liver, inflammation induced by chemical stress may raise interleukin-6 and activate the JAK2–STAT3 pathway, increasing hepcidin transcription. Oxidative stress may also stimulate NRF2, which can influence hepcidin-related regulatory elements. Excess hepcidin would reduce ferroportin, trapping iron in hepatocytes and macrophages. At the same time, the estrogen-like activity of bisphenols may act through estrogen receptor alpha and potentially suppress hepcidin expression, based partly on evidence from estrogenic regulation of iron metabolism and related environmental chemicals. Lower systemic hepcidin would stabilize ferroportin in intestinal cells, increasing iron absorption and altering the distribution of iron between the gut, blood and liver. The balance between these opposing signals may depend on dose, exposure duration, chemical structure and receptor abundance in each tissue. The authors call this proposed mismatch “hepcidin dyssynchrony,” but identify it as a working hypothesis rather than a settled mechanism.

The intestine adds another layer to the possible interaction. Iron availability strongly shapes the gut microbiome. During iron deficiency, increased intestinal uptake can leave less iron for microbes, favoring organisms able to produce siderophores, molecules that capture iron efficiently. During iron excess, oxidative chemistry may harm sensitive beneficial bacteria while allowing more stress-resistant pathobionts to expand. In either setting, the review describes possible reductions in bacteria associated with beneficial metabolites and increases in members of the Enterobacteriaceae family. Changes in short-chain fatty acids, including acetate, propionate and butyrate, may weaken signals that normally activate AMPK, support fatty-acid oxidation and restrain SREBP1c-driven lipogenesis. Lower butyrate may also reduce support for intestinal tight-junction proteins such as ZO-1 and occludin. A leakier intestinal barrier could permit more lipopolysaccharide to reach the liver through the portal circulation, where it activates Toll-like receptor 4 and NF-κB inflammatory signaling. Altered bile-acid metabolism may compound the effect by disturbing the FXR–FGF19/15 pathway, a key regulator of lipid and bile-acid homeostasis. These links remain biologically plausible, but the direction of cause and effect between iron imbalance, microbiome changes and MASLD is not yet clear.

The evidence base has important limitations that shape what can reasonably be concluded. Some preclinical experiments cited in the review used BPA doses of about 5 milligrams per kilogram per day, far above estimated median population exposure. Such studies can reveal molecular pathways and potential adverse outcomes, but their results cannot be transferred directly to human risk. Low-dose endocrine-disrupting chemicals may also produce non-monotonic dose responses, meaning that biological effects do not necessarily increase in a simple straight line as exposure rises. The review notes that the CLARITY-BPA program reported biological effects at several lower doses, although interpretation of low-dose findings remains an active scientific debate. Human studies have mainly examined associations between urinary or circulating bisphenol measurements and liver or metabolic outcomes, which cannot by themselves prove causation. Exposure is also usually mixed, involving multiple bisphenols, dietary factors, air pollutants and medications. The authors recommend population cohorts that measure bisphenol metabolites together with hepcidin, ferroportin-related markers, iron stores, liver fat and inflammatory indicators over time. They also call for physiologically based pharmacokinetic modeling, stable-isotope iron tracing, multi-omics analysis and studies using controlled environmental concentrations.

If the proposed pathway is confirmed, it could broaden strategies for preventing or treating environmentally influenced MASLD. Possible research directions include blocking inappropriate GPER signaling, restoring antioxidant capacity, correcting iron distribution or modifying gut microbial metabolism. Iron chelation or supplementation would require particular caution because both deficiency and excess can worsen metabolic injury, and treatment would need to be guided by reliable measures of tissue and systemic iron rather than by a single blood value. Microbiome-directed approaches might focus on preserving short-chain-fatty-acid production and intestinal barrier function, but they remain experimental for this application. For now, the review’s main contribution is conceptual: it places iron homeostasis at the intersection of endocrine disruption, redox biology, lipid metabolism and the gut–liver axis. The authors do not claim that bisphenols alone explain MASLD, a disease with many interacting causes. Instead, they suggest that common environmental chemicals may act as metabolic modifiers whose effects are amplified by obesity, insulin resistance, diet or pre-existing inflammation. Establishing whether this mechanism operates at real-world exposure levels will require direct human evidence, but the proposed framework offers specific molecular and clinical markers that future studies can test.

Subject of Research: Bisphenol-related disruption of iron homeostasis in metabolic dysfunction-associated steatotic liver disease

Article Title: Bisphenols perturb systemic iron homeostasis and fuel the pathogenesis of metabolic dysfunction-associated steatotic liver disease

Article References: Xu, J., Xu, H., Qi, R., Li, Y., Zhou, Z., Wu, W., Tian, Z., & Tang, Z. (2026). Bisphenols perturb systemic iron homeostasis and fuel the pathogenesis of metabolic dysfunction-associated steatotic liver disease. Discover Toxicology, 3(1), Article 19. https://doi.org/10.1007/s44339-026-00065-x

Image Credits: AI Generated

DOI: 10.1007/s44339-026-00065-x

Keywords: Bisphenols, Iron homeostasis, MASLD, Hepcidin, Ferroptosis, Oxidative stress, Gut microbiome, Liver disease, perturb, systemic, iron, homeostasis