Regulator Of Iron Homeostasis Research Articles

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

Suppressing ferroptosis via modulating FTH1 by silybin for treatment of renal fibrosis.

BackgroundType 1 myocardial infarction (T1MI) is an acute ischemic event triggered by the rupture of a coronary atherosclerotic plaque. The pathogenesis of T1MI is highly complex, involving disturbances in iron metabolism, cell apoptosis, immune activation, and inflammatory responses. In recent years, ferritinophagy, a novel autophagic mechanism regulating iron homeostasis, has attracted increasing attention for its role in cardiovascular diseases. However, its precise involvement in T1MI remains to be fully elucidated. This study aims to systematically analyse the mechanism of ferritinophagy in T1MI and explore its potential connection to immune and inflammatory responses.MethodsExosomes were isolated from coronary thrombi of T1MI patients and subjected to comprehensive transcriptomic profiling. Differentially expressed lncRNAs and mRNAs were validated through functional assays, including RIP, FISH, ChIP, and m6A methylation experiments. Cardiomyocyte models and integrated bulk and single-cell RNA sequencing were used to clarify cellular context and regulatory networks, with particular emphasis on YTHDF family proteins. Bioinformatics analyses, including GO and KEGG, were employed for pathway annotation.ResultsElectron microscopy confirmed the presence of exosomes in coronary thrombi. Thrombus-derived exosomes (TEs) induced pronounced ferritinophagy in cardiomyocytes, evidenced by increased autophagosomes, ROS, apoptosis, and iron overload, with these effects ameliorated by the ferroptosis inhibitor Fer-1. Transcriptomic and functional analyses identified lncRNA FENDRR as highly enriched in TEs, with FENDRR and P53 acting in concert to regulate NCOA4 and system Xc–. Mechanistically, FENDRR directly binds P53, and both upregulate m6A modification in cardiomyocytes, specifically through upregulation of YTHDF1 and downregulation of YTHDF3. Inhibition of either FENDRR or P53 reverses these changes. Single-cell RNA-seq analysis revealed significant upregulation of TP53, NCOA4, and YTHDF1, alongside downregulation of YTHDF3 in macrophages from plaque tissue, linking ferritinophagy, autophagy, and immune-inflammatory responses.ConclusionThis study is the first to reveal the critical role of the “FENDRR–m6A–NCOA4” regulatory axis as a critical mediator of ferritinophagy in T1MI. It also suggests that immune cells may participate in the immune-inflammatory response associated with myocardial injury via ferritinophagy. Our research provides multi-omics evidence of the interaction between iron homeostasis, immunity, and inflammation in T1MI, offering potential therapeutic strategies for targeting ferritinophagy and related RNA modification pathways.

Iron is a vital cofactor for enzymes essential to many biological processes, yet in excess, it poses a danger to all living organisms. In order to ensure survival and proliferation under fluctuating environmental iron levels, bacteria evolve sophisticated regulatory systems to maintain iron homeostasis. Unlike master regulator Fur, a large portion of other players remains poorly defined. Here, we characterized the physiological impacts of atypical phosphorylation-independent response regulator SsoR of Shewanella oneidensis, a γ-proteobacterium renowned for metabolic versatility. By combining transcriptomics, proteomics, and transposon screening, we discovered that the SsoR loss impairs growth and decreases cytochrome c content under iron-limited conditions. Further investigations revealed that the defects can be attributed to lowered heme and iron levels, a consequence of elevated Fur production. Together, our findings suggest that SsoR and Fur constitute a derepressing-inhibiting oscillation system in maintaining iron homeostasis, providing a new composite view of regulator dynamics during the regulation of iron homeostasis in bacteria.IMPORTANCEShewanella comprises a large group of bacteria that are ubiquitous, ecologically widespread, and metabolically versatile, having enormous potential in biotechnology, environmental remediation, and energy production. These characteristics and applications are crucially determined by a myriad of iron-containing proteins, whose activity depends on the intricate regulation of iron homeostasis. Our study reveals that a derepressing-inhibiting oscillation system composed of Fur and atypical phosphorylation-independent response regulator SsoR plays a key role in the regulation of iron homeostasis at the transcription level. The loss of either results in altered production of the other, leading to disruption of iron homeostasis, which is harmful to the cell, especially under iron-limited conditions. This study deepens our understanding of the interacting dynamics of multiple regulators in iron homeostasis.

Rubella is typically a mild viral illness, but it can lead to severe complications when contracted during pregnancy, such as pregnancy loss or developmental defects in the fetus (congenital rubella syndrome). Therefore, it is crucial to develop and maintain protective immunity in women of childbearing age. In this study, we assessed the transcriptional factors associated with rubella-specific immune outcomes (IgG binding antibody and avidity, neutralizing antibody, and memory B cell ELISpot response) following a third MMR vaccine dose in women of reproductive age to identify key factors/signatures impacting the immune response. We identified baseline (Day 0) and differentially expressed (Day 28–Day 0) genes associated with several RV-specific immune outcomes, including the transferrin receptor 2 (TFR2), which is an important factor regulating iron homeostasis and macrophage functional activity, and a close functional homolog of TFR1, the cellular receptor of the New World hemorrhagic fever arenaviruses. We also identified enriched KEGG pathways, “cell adhesion molecules”, “antigen processing and presentation”, “natural killer cell-mediated cytotoxicity”, and “immune network for IgA production”, relevant to immune response priming and immune activation to be associated with RV-specific immune outcomes. This study provides novel insights into potential biomarkers of rubella-specific immunity in women of childbearing age.

Osteosarcoma (OS), a highly malignant primary bone tumor, is characterized by early metastasis, drug resistance, and a resultant poor prognosis, leading to significant disability and mortality. While diverse treatment modalities exist, their therapeutic efficacy remains limited, underscoring the urgent need to investigate effective targeted therapies. Sulfasalazine (SAS), a commonly used anti-inflammatory drug prescribed for nonspecific gastrointestinal diseases, autoimmune rheumatic diseases, ankylosing spondylitis, and various skin conditions, has recently garnered attention for its potential as an anti-tumor agent, specifically its ability to induce ferroptosis, a novel form of regulated cell death. This presents a promising new avenue for OS treatment. Ferroptosis plays a critical role in the malignant progression of OS by regulating iron homeostasis and oxidative stress. To explore the potential of SAS to induce ferroptosis in OS cells, we employed a combined approach of network pharmacological analysis and molecular docking simulations. Network pharmacological analysis identified significant overlap among key target genes of SAS, ferroptosis, and OS, suggesting a multifaceted mechanism of action. Molecular docking simulations further corroborated the hypothesis that SAS targets ferroptosis pathways in OS, solidifying the rationale for further investigation. Our results demonstrate that SAS significantly inhibited the proliferation and migration of OS cells, inducing apoptosis and effectively attenuating their malignant progression. Notably, SAS-treated OS cells displayed hallmarks of ferroptosis, including iron accumulation, elevated levels of malondialdehyde and reactive oxygen species, and reduced levels of glutathione and superoxide dismutase. To confirm the involvement of ferroptosis, we treated SAS-exposed OS cells with the ferroptosis inhibitors DFO, Fer-1, and Lip-1, which reversed the inhibitory effects of SAS on cell activity, further supporting the conclusion that SAS triggers ferroptosis in these cells. We additionally observed that SAS decreased mitochondrial membrane potential in OS cells, potentially indicating mitochondrial damage during ferroptosis. Mechanistically, we found that SAS induced ferroptosis by downregulating the expression of NRF2, subsequently decreasing the expression of the light chain subunit of the cysteine/glutamate transporter system Xc- (SLC7A11) and glutathione peroxidase 4. Collectively, these findings demonstrate that SAS triggers ferroptosis through the NRF2/SLC7A11/GPX4 signaling axis, thereby inhibiting the biological activity of OS cells. This research provides a strong experimental basis for the potential of SAS as a candidate drug for OS treatment and offers a novel targeted therapeutic strategy for this disease.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-13324-5.

ABSTRACT Ferroptosis remains an underexamined iron- and lipid peroxides-driven cell death modality despite its importance to several human and plant diseases and to immunity thereof. Here, we utilized chemical cell biology, molecular genetics and biochemical analyses to gain insights into how the fungal pathogen Magnaporthe oryzae undergoes ferroptosis strictly in the spore cells to successfully transit to infectious development. We reveal a complex functional interdependency and crosstalk between intrinsic ferroptosis and autophagy-mediated mitochondrial degradation. Mechanistically, the requirement of mitophagy for ferroptotic cell death was attributed to its ability to maintain a pool of metabolically active mitochondria. Pharmacological disruption of the electron transport chain or membrane potential led to complete inhibition of ferroptosis, thus simulating the loss of mitophagy phenotypes. Conversely, increased mitochondrial membrane potential in a mitophagy-defective mutant alleviated the ferroptosis defects therein. Graded inhibition of mitochondrial coenzyme Q biosynthesis with or without ferroptosis inhibitor liproxstatin-1 distinguished its antioxidant function in such regulated cell death. Membrane potential-dependent regulation of ATP synthesis and iron homeostasis, as well as dynamics of tricarboxylic acid cycle enzyme AcoA (aconitase A) in the presence or absence of mitophagy, mitochondrial poisoning or iron chelation further linked mitochondrial metabolism to ferroptosis. Last, we present an important bioenergetics- and redox-based mitochondrial regulon essential for intrinsic ferroptosis and its precise role in fungal pathogenesis leading up to the establishment of the devastating rice blast disease. Abbreviation: 4-CBA: 4 chlorobenzoic acid; AcoA: aconitase A; Atg24: autophagy related 24; CoQ: coenzyme Q; CPX: ciclopirox olamine; ETC: electron transport chain; GSH: glutathione; Gpx4: glutathione peroxidase 4; HPI: hours post inoculation; MMP: mitochondrial membrane potential; MitoQ: Mitoquinone; ROS: reactive oxygen species; TCA: tricarboxylic acid

Male infertility, as a globally significant reproductive health issue, remains idiopathic in over 40% of cases. Reproductive disorders in males induced by environmental pollutants, such as di(2-ethylhexyl) phthalate (DEHP), have garnered considerable attention in recent years. DEHP induces testicular oxidative stress and ferroptosis via its active metabolite MEHP, thereby leading to spermatogenic dysfunction. Lycium barbarum polysaccharide (LBP), a traditional food and medicine homologous substance, exhibits potential antioxidant and reproductive protective properties. However, the underlying mechanism by which LBP intervenes in the toxicity induced by DEHP remains to be elucidated. This study explored the protective effect and molecular mechanism of LBP on DEHP-induced testicular injury through in vivo and in vitro experiments. The result showed that DEHP exposure (150 mg/L in free drinking water for 6 weeks) significantly decreased testicular weight, sperm concentration, and sperm motility in mice, while DEHP exposure induced pathological damage to testicular tissue, as evidenced by cavitation of seminiferous tubules, reduced numbers of spermatocytes, and vacuolar degeneration of Sertoli cells. However, LBP (450 mg/L) treatment significantly reversed testicular damage and sperm parameters. In vitro, MEHP reduced the viability of GC2 cells (spermatocyte cell line) and TM4 cells (Sertoli cell line), and LBP significantly restored cell activity. Mechanistically, exposure to DEHP/MEHP results in iron overload (elevated levels of free Fe2+), lipid peroxidation (increased MDA and reduced GSH), and dysregulated expression of key proteins involved in ferroptosis and iron homeostasis within the testis and cells. Furthermore, it was demonstrated that when NRF2 was specifically inhibited by ML385 or silenced via siRNA, the protective effects of LBP were abrogated, thereby validating the critical role of NRF2 in the regulation of iron homeostasis by LBP. In conclusion, LBP mitigates DEHP-induced testicular injury by activating NRF2 to regulate iron homeostasis in Sertoli cells and spermatocytes cells. This study not only offers a potential strategy for the prevention and treatment of male reproductive disorders caused by DEHP exposure, but also underscores the reproductive protective effects and application prospects of LBP in this context.

Macranthoside B (MB) is a saponin compound extracted from hon-eysuckle that has been reported to exhibit significant medicinal values, particularly anti-tumor activities. This study aimed to evaluate the anticancer efficacy of MB in treating adenocarci-noma of the esophagogastric junction (AEG) and elucidate its underlying mechanisms. Three AEG cell lines and normal gastric epithelial cells were used to assess the an-ticancer activity of MB in vitro. A series of experiments, including RNA sequencing (RNA-seq) analysis, transmission electron microscopy (TEM), immunofluorescence, and western blot assay, were conducted to validate the molecular mechanisms by which MB may mediate these physiological changes. Finally, we used shRNA assays to silence the key gene driving these changes and examined the expression of molecules involved in the affected pathways. MB exhibited significant anti-AEG cell activity with IC50 values ranging from 9.5 to 12.7 μM. RNA-seq results indicated that MB treatment in AEG cells significantly altered mRNA levels of autophagy- and ferroptosis-related genes. Further experiments revealed that MB treatment led to the up-regulation of lipid reactive oxygen species (Lip-ROS), oxidative stress-related pathway genes, and LC3B-labeled autophagic vesicles in AEG cells. Moreover, MB mediated NCOA4-dependent ferritinophagy, disrupting iron homeostasis and causing subsequent ferroptosis. We further confirmed that the intrinsic connection between autophagy and ferroptosis was due to the inhibition of NRF2 by MB. The inhibition of NRF2 by MB triggered transcriptional repression of its downstream effector molecules HERC2 and VAMP8, thus stabilizing NCOA4. This study demonstrated MB to inhibit AEG cell growth by regulating iron ho-meostasis and inducing ferroptosis through the inhibition of NRF2, providing a basis for the development of novel drugs for AEG treatment.

Glucose deprivation-restoration induces labile iron overload and ferroptosis in renal tubules through V-ATPase-mTOR axis-mediated ferritinophagy and iron release by TPC2.

Unraveling the nexus: Sleep's role in ferroptosis and health.

Exosomal miRNA-188-3p derived from cancer-associated fibroblasts promotes ferroptosis in cervical cancer: Medical biothermal image analysis.

Background: Disruption of iron homeostasis is widely recognized as a key contributor to the pathogenesis of cardiomyopathy and heart failure. Protein phosphatase 2A (PP2A), a crucial serine/threonine phosphatase, has recently gained an increased appreciation due to its functional importance in cardiovascular biology. However, a complete understanding of PP2A function in the pathology of takotsubo syndrome (TTS) is lacking. Objective: To characterize the functional role of PP2A in the regulation of cardiac iron homeostasis and TTS progression. Methods: Using a single high-dose injection of isoprenaline (ISO; 400 mg/kg) in a TTS-like mouse model, gain- and loss-of-function studies were performed to understand the role of PP2A in TTS. In addition, in vitro studies in H9C2 cardiomyocytes and primary human cardiac myocytes were conducted to study the underlying molecular mechanisms by which PP2A impacts TTS. Results: In murine TTS, a profound decrease of PP2A activity in cardiomyocytes (as indicated by diminished methylation of the PP2A catalytic subunit) was observed. This was accompanied by molecular features typical of ferroptosis, including increased cardiac iron levels and increased lipid peroxidation. Furthermore, myocardial-specific knockout of PP2A in mice exacerbated ferritinophagy, resulting in the accumulation of labile iron and further disrupted mitochondrial homeostasis, thereby aggravating cardiomyocyte ferroptosis. Conversely, administration of the lead small molecule activator of PP2A (SMAP), DT-061, increased methylation of the PP2A catalytic subunit, inhibited cardiomyocyte ferroptosis, alleviated acute cardiac injury, and prevented TTS progression. Conclusions: These results demonstrate that PP2A plays a critical role in protecting against cardiac ferroptosis and acute heart failure, thereby providing a novel therapeutic target for the prevention and treatment of TTS.

Exploring the role of the CCAAT-binding complex in cell wall maintenance and biofilm formation in Candida albicans.

Thalassemia is a genetic disorder characterized by impaired hemoglobin synthesis. This disease is caused by mutations in the globin gene, leading to disrupted production of globin chains. As a result, the red blood cells produced are dysfunctional and have a shorter lifespan, causing anemia. This condition requires proper medical management, including blood transfusions and other treatments. One way to detect and monitor the progression of thalassemia is by using biochemical markers that can identify changes in the patient’s body. Therefore, the aim of this systematic literature review is to identify biochemical markers that can be used for the diagnosis and monitoring of thalassemia. The literature used in this study includes articles on human thalassemia research published in the last 10 years. Literature searches were conducted in several academic databases using relevant keywords such as “biochemical markers for thalassemia,” “diagnosis of thalassemia,” and “thalassemia monitoring.” Based on the search results, several biochemical markers related to thalassemia were identified, including hepcidin, ferritin, and lipid profile. Ferritin plays a role in monitoring iron levels, which are often elevated in thalassemia patients, while hepcidin regulates iron homeostasis in the body. Additionally, other components involved in thalassemia diagnosis and monitoring include Mean Corpuscular Volume (MCV), Mean Corpuscular Hemoglobin (MCH), Mean Corpuscular Hemoglobin Concentration (MCHC), and hemoglobin levels. The findings of this systematic literature review are expected to provide a comprehensive overview of biochemical markers that can be used in the diagnosis and monitoring of thalassemia. By identifying relevant markers, it is hoped that more accurate and effective diagnostic methods will be developed in the future, leading to better monitoring of thalassemia patients.

The ability to acquire iron and maintain iron homeostasis is crucial for the virulence of the human pathogenic fungus Cryptococcus neoformans. This study investigates the role of Bud32, a core virulence kinase and component of the KEOPS complex, within the iron regulatory network of C. neoformans. We used gene deletion techniques to study the phenotypic effects of BUD32 gene knockout and conducted proteomic and metabolomic analyses to assess changes in protein expression and metabolite levels in the mutant. Additionally, we performed in vivo phosphoproteomics analysis to evaluate Bud32 impact on iron regulatory proteins. Our findings revealed that deletion of BUD32 gene significantly impaired growth in iron-limiting environments, leading to notable alterations in the expression of iron transport and iron-sulfur cluster (ISC)-containing proteins. Specifically, Bud32 was shown to modulate ISC assembly and influence the activity of key iron-sulfur binding proteins, including Grx4, Cir1, and HapX. Metabolic profiling indicated changes in 696 metabolites, with reductions in biliverdin levels. Additionally, BUD32 gene deletion resulted in widespread changes in the phosphorylation status of numerous proteins, including the iron regulators Cir1 and Rim101. These findings provide evidence for the involvement of the kinase Bud32 in regulating iron homeostasis in C. neoformans, thereby contributing to our understanding of its virulence mechanisms.

ABSTRACTThe lack of a mechanistic understanding of the environmental plasticity of secondary cell wall (SCW) biosynthesis restricts large‐scale biomass and bioenergy production on marginal lands. Using Populus (poplar), a key bioenergy crop, we discovered that iron deprivation, a prevalent abiotic stress on marginal lands, stimulates SCW biosynthesis in stems. We identified the transcription factor PtrbHLH011 as a critical regulator underlying this response. Through integrated analyses involving phenotypic characterisation of PtrbHLH011 knockout and overexpression plants, functional genomics and molecular investigations, we established that PtrbHLH011 functions as a central regulator of SCW biosynthesis, iron homeostasis and flavonoid biosynthesis by directly repressing essential genes in these pathways. Iron deprivation downregulates PtrbHLH011 expression, subsequently activating these biosynthetic pathways. Notably, cytosine base editing‐based knockout of PtrbHLH011 significantly enhanced plant growth, yielding up to a 110% increase in stem diameter and a 300% increase in leaf iron content. These findings present a novel regulatory mechanism linking environmental iron availability to SCW biosynthesis and illustrate a practical strategy to improve biomass yield on iron‐deficient marginal lands. Furthermore, our mechanistic insights into PtrbHLH011 target recognition and regulation provide a valuable foundation for precise manipulation of gene regulatory networks, facilitating the development of high‐performance bioenergy crops adapted to marginal environments.

Background: Chelation therapy plays a crucial role in the management of beta-thalassemia major, a genetic disorder characterized by defective hemoglobin production, resulting in chronic anaemia and iron overload due to frequent blood transfusions. Over time, excess iron accumulates in vital organs, causing significant damage, which is why chelation therapy, aimed at removing excess iron, is a standard treatment approach. However, this therapy's impact extends beyond iron regulation, influencing various physiological processes, including the regulation of hepcidin, ferritin, and fertility hormones. Hepcidin is a key regulator of iron homeostasis, while ferritin serves as an iron storage protein that reflects the body’s iron levels. Understanding the complex interplay between chelation therapy and these biomarkers is critical for improving the management of beta-thalassemia major and mitigating potential long-term complications OBJECTIVES: This study aims to evaluate the impact of chelation therapy on iron regulation and fertility hormones in females with beta thalassemia major. Methods: A cross-sectional case–control study was conducted over 12 months from January to June 2024 involving 180 women (90 healthy controls and 90 patients) aged 16-40 years. Patients were randomly selected according to the specific inclusion and exclusion criteria. The serum levels of hepcidin hormone, ferritin, and fertility hormones were measured by Enzyme-Linked Immunosorbent Assay. SPSS Program was used to code, enter, and process the gathered data. RESULTS: Serum hepcidin levels in patients with good compliance did not differ significantly from those with poor compliance while Ferritin levels were significantly lower in good compliance patients (769.16±176.36) vs. poor compliance (868.62±140.81), p=0.005. LH and prolactin showed non-significant increases in good compliance (1.40±0.77, 2.55±1.11) vs. poor compliance (1.39±0.86, 2.28±1.08). FSH and estradiol levels were significantly higher in good compliance patients (2.51±1.20, 11.65±0.95) compared to poor compliance (1.87±0.95, 11.20±1.04), p<0.05. CONCLUSIONS: Patients with better compliance to iron chelation had higher hepcidin, lower ferritin, and improved FSH and E2 levels, emphasizing the importance of adherence to therapy.

Preeclampsia (PE) is a pregnancy-specific hypertensive disorder characterized by systemic inflammation, endothelial dysfunction, and placental insufficiency. While inadequate trophoblast invasion and impaired spiral artery remodeling have long been recognized as central to its pathogenesis, emerging evidence underscores the critical roles of dysregulated iron metabolism and its crosstalk with immune responses, particularly macrophage-mediated inflammation, in driving PE development. This review systematically explores the dynamic changes in iron metabolism during pregnancy, including increased maternal iron demand, placental iron transport mechanisms, and the molecular regulation of placental iron homeostasis. We further explore the contribution of ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, to trophoblast dysfunction and pregnancy-related diseases, including PE. Macrophages, pivotal immune regulators at the maternal-fetal interface, exhibit distinct polarization states that shape tissue remodeling and immune tolerance. We outline their origin, distribution, and polarization in pregnancy, and emphasize their aberrant phenotype and function in PE. The bidirectional crosstalk between iron and macrophages is also dissected: iron shapes macrophage polarization and function, while macrophages reciprocally modulate iron homeostasis. Notably, excessive reactive oxygen species (ROS) and pro-inflammatory cytokines secreted by M1-polarized macrophages may exacerbate trophoblast ferroptosis, amplifying placental injury. Within the context of PE, we delineate how iron overload and macrophage dysfunction synergize to potentiate placental inflammation and oxidative stress. Key iron-responsive immune pathways, such as the HO-1/hepcidin axis and IL-6/TNF-α signaling, are discussed in relation to disease severity. Finally, we highlight promising therapeutic strategies targeting the iron-immune axis, encompassing three key modalities-iron chelation therapy, precision immunomodulation, and metabolic reprogramming interventions-which may offer novel avenues for PE prevention and treatment.

Iron overload and ferroptosis are associated with intestinal ischemia and reperfusion (II/R)-induced acute lung injury (ALI). However, the mechanisms underlying the regulation of iron homeostasis remain unclear. Nrf2 regulates cellular iron homeostasis; nonetheless, its impact on ALI pathology and its underlying mechanism of action requires further investigation. Ubiquitin ligase E3B (UBE3B) plays a critical role in the proteasome pathway, which is essential for protein turnover and ubiquitin-mediated signaling. A recent study found that UBE3B plays a role in oxidative stress; nevertheless, it remains unknown whether its role is related to Nrf2. Furthermore, the exact role of UBE3B in ALI and its underlying mechanism remain largely uncharacterized. In the present study, immunohistochemical analysis of UBE3B expression in type II alveolar epithelial cells (AECII) was conducted, and its expression was found to be decreased in II/R-ALI. Western blot analysis indicated that UBE3B hypoactivation may aggravate oxidative stress, thereby promoting ALI. Moreover, UBE3B was involved in iron metabolism dysfunction and ferroptosis. UBE3B deficiency enhanced the process of nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy and increased ferrous ion content, whereas overexpression of UBE3B reversed the harmful effects of Nrf2 knockdown on AECII, which may promote AECII ferroptosis. This study highlights the role of the Nrf2/UBE3B/NCOA4 axis in AECII ferroptosis and II/R-ALI pathogenesis, suggesting that Nrf2 activation may be a promising strategy for ALI treatment.