The complex etiological factors associated with metabolic dysfunction-associated fatty liver disease (MAFLD), including perturbed iron homeostasis, and the unclear nature by which they contribute to disease progression have resulted in a limited number of effective therapeutic interventions. Here, we report that patients with metabolic dysfunction-associated steatohepatitis (MASH), a pathological subtype of MAFLD, exhibit excess hepatic iron and that it has a strong positive correlation with disease progression. FerroTerminator1 (FOT1) effectively reverses liver injury across multiple MASH models without notable toxic side effects compared with clinically approved iron chelators. Mechanistically, our multi-omics analyses reveal that FOT1 concurrently inhibits hepatic iron accumulation and c-Myc-Acsl4-triggered ferroptosis in various MASH models. Furthermore, MAFLD cohort studies suggest that serum ferritin levels might serve as a predictive biomarker for FOT1-based therapy in MASH. These findings provide compelling evidence to support FOT1 as a promising novel therapeutic option for all stages of MAFLD and for future clinical trials.

Heme is essential for a variety of proteins involved in vital physiological functions in the body, such as oxygen transport, drug metabolism, biosynthesis of steroids, signal transduction, antioxidant defense and mitochondrial respiration. However, free heme is potentially cytotoxic due to the capacity of heme iron to promote the oxidation of cellular molecules. The liver plays a central role in heme metabolism by significantly contributing to heme synthesis, heme detoxification, and recycling of heme iron. Conversely, enzymatic defects in the heme biosynthetic pathway originate multisystemic diseases (porphyrias) that are highly associated with liver damage. In addition, there is growing evidence that heme contributes to the outcomes of inflammatory, metabolic and malignant liver diseases. In this review, we summarize the contribution of the liver to heme metabolism and the association of heme dyshomeostasis with liver disease.

Iron is an important micronutrient involved in cell biology through vital reactions. We examined the correlations between iron metabolism parameters and the course of invasive fungal sinusitis. Patients with invasive fungal sinusitis were enrolled. Serum iron and ferritin levels, total iron-binding capacity, and transferrin saturation were measured at the initiation of treatment. Patients were followed for 6 months, and the clinical course was categorised as improvement or worsening/death. A total of 35 patients were enrolled. The average ferritin levels in mucormycosis patients was 944.9 ng/ml, versus 110.7 ng/ml for aspergillosis patients. Iron levels were significantly lower in mucormycosis than in aspergillosis (29.14 µg/dl vs. 68.55 µg/dl). Total iron-binding capacity was significantly different between the two groups (16.76 µg/dl vs. 330.36 µg/dl). After 6 months, improvement, worsening, and death were noted for 18, 8, and 9 patients, respectively. Higher iron levels and lower ferritin levels were linked with improvement. Total iron-binding capacity was significantly higher in improved patients (2314 vs. 151). Iron metabolism parameters play significant roles in the preemptive judgment of the course of fungal sinusitis. Based on these findings, studies on drugs affecting iron metabolism should be conducted.

Sickle cell disease (SCD) is an inherited haemoglobinopathy associated with significant morbidity and mortality. Automated red blood cell exchange (aRCE) plays a key role in managing SCD, eliciting both therapeutic and prophylactic effects. The ideal post-apheresis Ht target for chronic aRCE treatment is not yet unanimously recognized, as well as iron homeostasis can be different among patients. Ross et al. reported their experience on the chronic management of SCD patients undergoing aRCE with a final post-exchange Ht higher than the value commonly adopted, analysing red blood cell transfusion requirements and iron-related outcomes in the study population. Commentary on: Ross et al. Automated red blood cell exchange with a post-procedure haematocrit targeted at 34% in the chronic management of sickle cell disease. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19674.

Iron deposition and myelin loss are observed in the brain with aging, and iron accumulation is suggested to be involved in myelin damage. However, the exact mechanism of iron deposition with aging remains unclear. This study was aimed to determine whether expanded visceral adipose tissue contributes to iron deposition and myelin loss by inducing hepcidin in the brains of aged male mice. Compared with young adult mice, levels of hepcidin in the brain, epididymal adipose tissue, and circulation were increased in aged mice, which had expanded visceral adipose tissue with inflammation. An increase in expressions of ferritin, an indicator of intracellular iron status, was accompanied by decreased levels of proteins related to myelin sheath in the brains of aged mice. These age-related changes in the brain were improved by visceral fat removal. In addition, IL-6 level, activation of microglia/macrophages, and nuclear translocation of phosphorylated Smad1/5 (pSmad1/5) inducing hepcidin expression were reduced in the brains of aged mice after visceral fat removal, accompanied by decreases of pSmad1/5- and ferritin-positive microglia/macrophages and mature oligodendrocytes. These findings indicate that visceral adiposity contributes to hepcidin-mediated iron deposition and myelin loss with inflammation in the aged brain. Our results support the importance of preventing visceral adiposity for maintaining brain health in older individuals.

Understanding the role of iron in ethanol-derived hepatic stress could help elucidate the efficacy of dietary or clinical interventions designed to minimize liver damage from chronic alcohol consumption. We hypothesized that normal levels of iron are involved in ethanol-derived liver damage and reduced dietary iron intake would lower the damage caused by ethanol. We used a pair-fed mouse model utilizing basal Lieber-DeCarli liquid diets for 22 weeks to test this hypothesis. In our mouse model, chronic ethanol exposure led to mild hepatic stress possibly characteristic of early-stage alcoholic liver disease, seen as increases in liver-to-body weight ratios. Dietary iron restriction caused a slight decrease in non-heme iron and ferritin (FeRL) expression while it increased transferrin receptor 1 (TfR1) expression without changing ferroportin 1 (FPN1) expression. It also elevated protein lysine acetylation to a more significant level than in ethanol-fed mice under normal dietary iron conditions. Interestingly, iron restriction led to an additional reduction in nicotinamide adenine dinucleotide (NAD+) and NADH levels. Consistent with this observation, the major mitochondrial NAD+-dependent deacetylase, NAD-dependent deacetylase sirtuin-3 (SIRT3), expression was significantly reduced causing increased protein lysine acetylation in ethanol-fed mice at normal and low-iron conditions. In addition, the detection of superoxide dismutase 1 and 2 levels (SOD1 and SOD2) and oxidative phosphorylation (OXPHOS) complex activities allowed us to evaluate the changes in antioxidant and energy metabolism regulated by ethanol consumption at normal and low-iron conditions. We observed that the ethanol-fed mice had mild liver damage associated with reduced energy and antioxidant metabolism. On the other hand, iron restriction may exacerbate certain activities of ethanol further, such as increased protein lysine acetylation and reduced antioxidant metabolism. This metabolic change may prove a barrier to the effectiveness of dietary reduction of iron intake as a preventative measure in chronic alcohol consumption.

Inflammatory bowel diseases (IBD) are complex disorders. Iron accumulates in the inflamed tissue of IBD patients, yet neither a mechanism for the accumulation nor its implication on the course of inflammation are known. We hypothesized that the inflammation modifies iron homeostasis, affects tissue iron distribution and that this in turn perpetuates the inflammation. This study analyzed human biopsies, animal models and cellular systems to decipher the role of iron homeostasis in IBD. We found inflammation-mediated modifications of iron distribution, and iron-decoupled activation of the iron regulatory protein (IRP)1. To understand the role of IRP1 in the course of this inflammation-associated iron pattern, a novel cellular co-culture model was established, that replicated the iron-pattern observed in vivo, and supported involvement of nitric oxide in the activation of IRP1 and the typical iron pattern in inflammation. Importantly, deletion of IRP1 from an IBD mouse model completely abolished both, the misdistribution of iron and intestinal inflammation. These findings suggest that IRP1 plays a central role in the coordination of the inflammatory response in the intestinal mucosa and that it is a viable candidate for therapeutic intervention in IBD.

Iron metabolism has emerged as a promising target for cancer therapy; however, the innate metabolic compensatory capacity of cancer cells significantly limits the effectiveness of iron metabolism therapy. Herein, bioactive gallium sulfide nanodots (GaSx), with dual functions of \"reprogramming\" and \"interfering\" iron metabolic pathways, were successfully developed for tumor iron metabolism therapy. The constructed GaSx nanodots ingeniously harness hydrogen sulfide (H2S) gas, which is released in response to the tumor microenvironment, to reprogram the inherent transferrin receptor 1 (TfR1)-ferroportin 1 (FPN1) iron metabolism axis in cancer cells. Concurrently, the gallium ions (Ga3+) derived from GaSx act as a biochemical \"Trojan horse\", mimicking the role of iron and displacing it from essential biomolecular binding sites, thereby influencing the fate of cancer cells. By leveraging the dual mechanisms of Ga3+-mediated iron disruption and H2S-facilitated reprogramming of iron metabolic pathways, GaSx prompted the initiation of a paraptosis-apoptosis hybrid pathway in cancer cells, leading to marked suppression of tumor proliferation. Importantly, the dysregulation of iron metabolism induced by GaSx notably increased tumor cell susceptibility to both chemotherapy and immune checkpoint blockade (ICB) therapy. This study underscores the therapeutic promise of gas-based interventions and metal ion interference strategies for the tumor metabolism treatment.

Alkaloids have remarkable biological and pharmacological properties and have recently garnered extensive attention. Various alkaloids, including commercially available drugs such as berberine, substantially affect ferroptosis. In addition to the three main pathways of ferroptosis, iron metabolism, phospholipid metabolism, and the glutathione peroxidase 4-regulated pathway, novel mechanisms of ferroptosis are continuously being identified. Alkaloids can modulate the progression of various diseases through ferroptosis and exhibit the ability to exert varied effects depending on dosage and tissue type underscores their versatility. Therefore, this review comprehensively summarizes primary targets and the latest advancements of alkaloids in ferroptosis, as well as the dual roles of alkaloids in inhibiting and promoting ferroptosis.

Ferroptosis, a form of regulated cell death characterized by iron-dependent phospholipid peroxidation, has emerged as a focal point in the field of cancer therapy. Compared with other cell death modes such as apoptosis and necrosis, ferroptosis exhibits many distinct characteristics in the molecular mechanisms and cell morphology, offering a promising avenue for combating cancers that are resistant to conventional therapeutic modalities. In light of the serious side effects associated with current Fenton-modulating ferroptosis therapies utilizing exogenous iron-based inorganic nanomaterials, hijacking endogenous iron could serve as an effective alternative strategy to trigger ferroptosis through targeting cellular iron regulatory mechanisms. A better understanding of the underlying iron regulatory mechanism in the process of ferroptosis has shed light on the current findings of endogenous ferroptosis-based nanomedicine strategies for cancer therapy. Here in this review article, we provide a comprehensive discussion on the regulatory network of iron metabolism and its pivotal role in ferroptosis, and present recent updates on the application of nanoparticles endowed with the ability to hijack endogenous iron for ferroptosis. We envision that the insights in the study may expedite the development and translation of endogenous ferroptosis-based nanomedicines for effective cancer treatment.