Regulator Of Iron Homeostasis Research Articles

BackgroundUnderstanding bacterial responses to nutrient limitation is critical for developing targeted antimicrobial strategies. Sulfur starvation uniquely induces not only genes responsible for sulfur scavenging but also prominent antioxidant defenses. However, the biological rationale behind the simultaneous induction of antioxidants during sulfur limitation remains largely unexplored. Our study addresses this gap by integrating transcriptomic, proteomic, and targeted metabolomic data from Pseudomonas aeruginosa PAO1 grown under sulfur-free conditions.ResultsAs anticipated, transcripts and proteins involved in sulfur assimilation and metabolism—including members of the msu, ssu, and cys operons—were upregulated, along with key antioxidant enzymes such as Ohr, LsfA, and SodB. Unexpectedly, however, genes encoding iron uptake systems (pyoverdine, pyochelin, and heme metabolism operons) were markedly downregulated, while iron storage proteins (BfrB, Dps, and PA4880) were elevated, indicating an iron-replete metabolic state. Further targeted metabolic profiling and iron quantification assays confirmed reduced Fe acquisition and diminished extracellular levels of siderophore and phenazine metabolites. This shift in iron homeostasis correlated with the repression of multiple virulence factors regulated by Fur and PrrF, including quorum-sensing components, efflux pumps, and phenazine biosynthesis enzymes.ConclusionOur integrative analysis reveals that sulfur starvation critically regulates iron homeostasis by linking reduced Fe uptake to the induction of antioxidant defenses. This iron-buffering response likely mitigates oxidative damage from unincorporated Fe, representing a protective metabolic adaptation. Additionally, the concurrent attenuation of virulence pathways suggests that targeting sulfur metabolism could disrupt iron-dependent virulence gene regulation, offering therapeutic insights into nutritional immunity strategies. Collectively, our findings uncover a novel sulfur-iron axis that plays a central role in oxidative stress management and pathogenicity modulation in bacteria.Graphical abstractUsing high-throughput RNA-sequencing and proteomics techniques, we identified genes and metabolites differentially expressed during sulfur starvation in P. aeruginosa grown in minimal media. Additional experiments using a range of biophysical techniques were used to quantify select metabolites and Fe. Overall, we found that sulfur starvation induced an Fe-replete response, characterized by the repression of Fe uptake pathways and the upregulation of Fe storage genes.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12866-025-04442-1.

Hepcidin/HIF-1α is involved in the endogenous recovery and ferroptosis after cerebral ischemia in mice.

Elevated levels of serum hepcidin isomers in dogs with portosystemic shunt.

Artesunate induces ferroptosis in gastric cancer by targeting the TFRC-HSPA9 axis for iron homeostasis regulation.

BackgroundFerroptosis, caused by abnormal iron metabolism and lipid peroxidation, has been linked to pathogenic processes in several disorders. Its function and regulating mechanisms in periodontitis are still unclear, nevertheless. As a naturally derived phenolic diterpenoid molecule, carnosic acid (CA) serves multiple biological roles, including antioxidant, anti-inflammatory, and cytoprotective properties. Its potential for intervention in periodontitis and ferroptosis warrants further exploration.MethodsIn this investigation, we combined network pharmacology analysis with in vitro and in vivo experimental validation to systematically evaluate the mechanism of action of CA intervention in periodontitis. Through an intersectional analysis of drug targets, ferroptosis-related genes, and periodontitis-related genes, potential core targets were identified, and GO/KEGG enrichment analysis was performed. The results suggest that Nrf2 is at the core of the protein interaction network and is significantly enriched in antioxidant response and iron homeostasis regulation pathways. Subsequently, changes in ROS, MDA, GSH, SOD, Fe²⁺, and other indicators, as well as the expression of ferroptosis-related indicators (GPX4, SLC7A11, FTH1), were detected in LPS-induced RAW264.7 cell models and rat periodontal ligation models. The key role of Nrf2 was verified using the Nrf2-specific inhibitor ML385.ResultsNetwork pharmacology results indicate that ferroptosis is crucial in the potential mechanism of CA action on periodontitis. Nrf2 is the core regulatory molecule connecting CA, periodontitis, and ferroptosis. The experimental results revealed that CA dramatically lowered ROS and MDA levels in cells and periodontal tissues, inhibited the accumulation of Fe²⁺, elevated the contents of GSH and SOD, and GPX4, SLC7A11, and FTH1 expression. Mechanistic studies have found that CA restores the antioxidant and iron homeostasis regulatory system by activating the Nrf2/GPX4 signaling axis, thereby inhibiting the vicious cycle of ferroptosis. After Nrf2 was blocked by ML385, the anti-ferroptosis and anti-inflammatory effects of CA were significantly weakened.ConclusionThe current research is the first to elucidate that CA can alleviate periodontitis pathological damage by suppressing ferroptosis via activating the Nrf2/GPX4 signaling axis. This enriches the pharmacological action spectrum of CA and provides new targets and a theoretical basis for periodontitis intervention strategies based on ferroptosis regulation.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12903-025-07048-1.

Multilayered epigenetic regulation of iron homeostasis in plants: From chromatin remodeling to genome engineering.

Background: Recent studies suggest that erythroferrone (ERFE), an iron-regulating protein whose primary role is to inhibit hepcidin synthesis, may affect glucose and lipid metabolism, and its serum concentration is reduced in obese and diabetic individuals. The aim of this study was to evaluate the association of ERFE concentration with selected cardiometabolic risk factors in apparently healthy young adults. Methods: This preliminary study consisted of 122 (63 females, 59 males) normoglycemic, non-smoking subjects aged 25–40 years. In all participants, anthropometric measurements and the following laboratory tests were performed: fasting plasma glucose, glycated hemoglobin (HbA1c) and serum iron, lipid profile, insulin, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), C-reactive protein (CRP), ERFE and hepcidin. Results: The serum ERFE concentration was significantly lower in men compared to women (p = 0.009) and in subjects who were overweight (p < 0.001) and had abdominal obesity (p < 0.001). ERFE showed significant negative correlations with body mass index, waist–hip ratio, HbA1c, CRP, insulin, HOMA-IR and triglycerides. In the logistic regression analysis, ERFE was significantly associated with being overweight (OR = 0.051; p = 0.004), abdominal obesity (OR = 0.372; p < 0.001), HOMA-IR ≥ 2.0 (OR = 0.584; p = 0.013), CRP > 1 mg/L (OR = 0.648; p = 0.020) and triglycerides (OR = 0.521; p = 0.033). A relevant predominance in the prevalence of cardiometabolic risk factors was observed in subjects with ERFE levels in the first tertile (<1.35 ng/mL), compared to the third tertile (>2.19 ng/mL). Conclusions: Serum ERFE is inversely associated with being overweight, increased waist circumference, CRP, and markers of insulin resistance and lipid abnormalities, suggesting its potential relevance as a marker of early cardiometabolic risk in apparently healthy young adults.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized pathologically by degeneration of upper and lower motor neurons, ultimately leading to muscle weakness and respiratory failure. Lipocalin-2 (LCN2) is a secreted protein involved in lipid transport that plays a key role in inflammatory responses and the regulation of iron homeostasis. The role of LCN2 in ALS has attracted increasing attention, as significantly elevated LCN2 expression has been observed in the blood and postmortem tissues of ALS patients. Functionally, LCN2 participates in neuroinflammation, iron dysregulation, cell death, and peripheral immune immunity, proposing a central-peripheral linkage hypothesis mediated by LCN2. Clinically, LCN2 shows promise as both a biomarker and a therapeutic target, with multiple strategies demonstrating potential to mitigate ALS pathology. Moving forward, it is essential to integrate multi-omics to deeply decipher LCN2-mediated molecular networks, advance patient stratification, and accelerate its clinical translation.

Selective autophagy in type 2 diabetes-associated cognitive dysfunction: Insightful mechanisms and therapies.

Iron is indispensable for the vast majority of organisms, and iron homeostasis plays a pivotal role in both the physiology and pathogenesis of fungal pathogens. However, the underlying mechanisms by which iron homeostasis modulates fungal pathogenesis remain to be fully elucidated. We therefore focused on investigating the functions of mitochondrial iron transporter ClMrs3/4 in virulence. We conducted targeted gene deletions, expression analyses, biochemistry, and pathogenicity assays, demonstrating that ClMrs3/4 regulates appressorial development via maintenance of cellular iron balance in Curvularia lunata. ClMrs3/4 modulates virulence by influencing appressorial development in C. lunata, which is dependent on iron homeostasis. ClMrs3/4 controls nitric oxide (NO) balance via the nitrate (NO3 -) assimilation pathway by modulating cytoplasmic iron levels, a process crucial for turgor pressure accumulation within the appressoria independent of mitochondrial and cytoplasmic Fe-S cluster biosynthesis. Our findings underscore the conserved role of Mrs3/4 in iron homeostasis among pathogenic fungi and propose a novel mechanism by which iron homeostasis regulates virulence, particularly through the NO3 - assimilation pathway mediated by cytoplasmic iron levels to regulate appressorial development.

Aluminum exposure induces ferroptosis in spermatogenic cells of mice through iron overload and lipid peroxidation.

Cobalt Hexacyanoferrate Nanocatalysts Combat Acute Lung Injury via Ferroptosis-Based Regulation of Iron Homeostasis and Antioxidant Defenses

Gut microbiota metabolite Urolithin B inhibits chondrocyte ferroptosis by rewriting iron homeostasis via FGFR3/NCOA4/FTH1 axis, alleviating osteoarthritis.

Spinal cord injury (SCI) causes irreversible neurological damage largely due to secondary processes such as ferroptosis and inflammation response, which hinder functional recovery and lack effective targeted treatments. Ferroptosis, an iron-dependent form of cell death driven by oxidative stress, and a pro-inflammatory microenvironment contribute significantly to neuronal loss after SCI. To address these challenges, we developed MCPAD, an injectable, self-healing nanocomposite hydrogel incorporating metformin-loaded PLGA nanoparticles (Met@PLGA NPs) and phenol-derived dynamic cross-linked network (CPAD). This multifunctional platform enables targeted suppression of ferroptosis and immunomodulation. In vitro, MCPAD significantly enhanced neuronal viability by regulating iron homeostasis and upregulating antioxidant defenses. In vivo, it reduced reactive oxygen species (ROS) accumulation, glial scarring, and inflammatory cytokine expression, while promoting axonal regeneration and synaptic remodeling. Treated animals exhibited greatly improved locomotor recovery and tissue preservation. Biochemical assessments confirmed systemic biosafety. These findings demonstrate the therapeutic potential of MCPAD as a biological responsive platform that reprograms the injury microenvironment to support functional neural repair after SCI.

Intestinal hepcidin overexpression promotes iron deficiency anemia and counteracts iron overload via DMT1 downregulation.

ABSTRACTSymbiotic bacteria in the human intestinal microbiota provide many pivotal functions to human health and occupy distinct biogeographic niches within the gut. Yet the molecular basis underlying niche-specific colonization remains poorly defined. To address this, we conducted a time-resolved dual RNA-seq experiment to simultaneously monitor the transcriptional co-adaptations of human commensalBacteroides thetaiotaomicronand human gut epithelial cells in an anaerobe-epithelium co-culture system. Comparative transcriptomic analysis of mucus-associated versus supernatantBacteroidespopulations unveiled small RNAs (sRNAs) that are differentially regulated between spatially segregated subpopulations. Among these, we identified IroR as a key sRNA that facilitatesB. thetaiotaomicronadaptation to the mucus-rich, iron-limiting niche, partly by modulating expression of bacterial capsule genes. This work provides new insights into the spatiotemporal dynamics of gut colonization and underscores a previously underappreciated role for bacterial sRNAs in shaping mutualistic interactions between the human microbiota and the gut epithelium.

Excessive gestational weight gain (GWG) is associated with various adverse pregnancy outcomes, including disruption of placental function and fetal development. Iron transport through the placenta is crucial for fetal growth, and transferrin receptor 2 (TfR2) plays a key role in iron homeostasis. However, the effect of excessive GWG on placental TfR2 expression and neonatal iron parameters remains unclear. This study aimed to investigate the effect of excessive GWG on placental TfR2 expression and its association with neonatal iron levels, including cord blood serum iron levels and total iron-binding capacity. A prospective study was conducted with 90 pregnant women divided into 2 groups: 45 with normal weight gain and 45 with excessive GWG. Placental TfR2 expression was assessed via immunohistochemistry, whereas neonatal iron parameters were analyzed in umbilical cord blood using biochemical assays. Additionally, in silico analyses were performed to explore the molecular pathways linking TfR2 expression and iron homeostasis. Placental TfR2 expression was significantly increased in the excessive GWG group compared to controls, with high immunoreactivity observed in the trophoblastic layer, capillaries, and villous connective tissue. Neonates from mothers with excessive GWG had significantly higher cord blood serum iron levels (P = .025) and lower total iron-binding capacity levels (P = .017). Bioinformatics analysis revealed that TfR2 is involved in iron homeostasis regulation, and ferroptosis emerged as a potentially relevant pathway. Excessive GWG may be associated with altered placental iron transport and increased TfR2 expression, which could contribute to iron overload and involvement of ferroptosis-related pathways. However, the lack of direct ferroptosis markers such as GPX4, ACSL4, reactive oxygen species levels, or cell-death assays limits mechanistic confirmation. Further studies are required to validate the role of ferroptosis in this context.

The bone morphogenetic protein (BMP)-SMAD signaling pathway is central to regulating hepcidin, the master regulator of systemic iron homeostasis. We have previously demonstrated that BMP6, BMP2, and, to a lesser extent, BMP5 are the major ligands contributing to hepcidin and iron homeostasis regulation invivo. Hemojuvelin (HJV) and homeostatic iron regulator (HFE) are hepcidin modulators that are mutated in hereditary hemochromatosis. Although both HJV and HFE regulate hepcidin, at least partly, by functionally interacting with the BMP-SMAD pathway, the mechanisms are incompletely understood. Notably, both HJV and HFE can regulate hepcidin in a BMP6-independent manner. To understand whether HJV and HFE influence hepcidin regulation by BMP2 and/or BMP5, we investigated the iron phenotype of mice with combined mutations in endothelial Bmp2/Hjv and Bmp5/Hfe. We found that endothelial Bmp2/Hjv double knockout (KO) mice exhibit more severe hepcidin deficiency and iron overload than single endothelial Bmp2 or Hjv KO mice, similar to previous findings in mice with double endothelial Bmp2/Hfe KO and Bmp6/Hjv KO, or a functional loss of both Bmp6 and Hfe. Moreover, we found that iron completely fails to induce hepcidin in both endothelial Bmp2/Hjv and Bmp2/Hfe double KO mice. In contrast, a functional loss of BMP5 does not worsen hemochromatosis in Hfe KO mice. Together with other published data, these findings suggest a model whereby BMP2 and BMP6 can signal to hepcidin induction independently of HJV and HFE and vice versa. In contrast, BMP5, HJV, and HFE are all required for iron-mediated hepcidin regulation in the absence of BMP2 and BMP6.

Cisplatin (CDDP) is a widely used chemotherapeutic agent, but its off-target toxicity, including testicular damage, limits clinical use. Bioactive compounds may help mitigate chemotherapy-induced reproductive toxicity. This study investigates thymol’s role in modulating ferritinophagy to preserve reproductive function and steroidogenesis. Male Wistar rats were randomized to control, CDDP, thymol, or CDDP + thymol groups. Thymol (60 mg/kg) was given orally for 14 days, and CDDP (8 mg/kg) was administered intraperitoneally on day 7. Testicular function was assessed through hormonal analysis, sperm evaluation, and histopathology. Ferritinophagy, oxidative stress, and inflammatory markers were assessed to elucidate thymol’s chemoprotective mechanisms. Thymol co-administration preserved steroidogenesis, restored sperm quality, and maintained testicular architecture in CDDP-treated rats. Thymol suppressed ferritinophagy, reducing iron overload and mitigating reactive oxygen species (ROS)-induced cellular damage. Additionally, thymol activated the Keap1/Nrf2/HO-1 pathway, enhancing antioxidant defenses while downregulating inflammatory mediators (TNF-α, IL-6). Additionally, thymol enhanced CDDP’s selectivity toward cancer cells while reducing its toxicity to normal cells. This study provides evidence that thymol modulates ferritinophagy to attenuate CDDP-induced testicular toxicity, helping preserve reproductive function via regulation of iron homeostasis. These findings highlight thymol’s potential as an adjunct therapy to mitigate chemotherapy-associated reproductive damage while maintaining CDDP’s anticancer efficacy.

Propionate alleviated colitis by modulating iron homeostasis to inhibit ferroptosis and macrophage polarization.