Chilean salmon farming confronts persistent challenges, including climate change risks and pathogens, where the most prevalent diseases impacting Atlantic salmon are Caligidosis and Rickettsial Salmonid Septicemia (SRS). As a sustainable strategy, fish vaccines hold promise for preventing diseases and reducing the use of antibiotics. While most studies on Atlantic salmon responses to vaccines emphasize transcriptome profiling from tissues such as the liver, head kidney, and skin, blood cell transcriptomics to monitor immune response dynamics is emerging as a promising tool in salmon aquaculture. This study evaluated the Atlantic salmon blood cell transcriptome in response to vaccination and subsequent infection with the sea louse Caligus rogercresseyi and the intracellular bacterium Piscirickettsia salmonis. The vaccination trial included four groups: fish immunized with the recombinant IPath® vaccine and two commercial vaccines currently used in Chile for salmon production. (BlueGuard® and Alpha Ject LiVac® SRS), and the unvaccinated control group. The group vaccinated with IPath® showed a higher transcriptomic response than commercial vaccines. Additionally, all three groups significantly modulated genes associated with iron homeostasis and metabolism. Furthermore, the HIF-1 signaling pathway and ferroptosis were notably activated in the IPath® group, suggesting a potential role of IPath® in the hypoxia response and cell death. This research highlights the effectiveness of using Atlantic salmon blood cells to assess immune responses, offering valuable insights into the fish immune system without resorting to lethal sampling.

The discovery of ferroptosis has brought a revolutionary breakthrough in heart failure treatment, and natural products, as a significant source of drug discovery, are gradually demonstrating their extraordinary potential in regulating ferroptosis and alleviating heart failure symptoms. In addition to chemically synthesized small molecule compounds, natural products have attracted attention as an important source for discovering compounds that target ferroptosis in treating heart failure.

Systematically summarize and analyze the research progress on improving heart failure through natural products' modulation of the ferroptosis pathway.

By comprehensively searching authoritative databases like PubMed, Web of Science, and China National Knowledge Infrastructure with keywords such as "heart failure", "cardiovascular disease", "heart disease", "ferroptosis", "natural products", "active compounds", "traditional Chinese medicine formulas", "traditional Chinese medicine", and "acupuncture", we aim to systematically review the mechanism of ferroptosis and its link with heart failure. We also want to explore natural small-molecule compounds, traditional Chinese medicine formulas, and acupuncture therapies that can inhibit ferroptosis to improve heart failure.

In this review, we not only trace the evolution of the concept of ferroptosis and clearly distinguish it from other forms of cell death but also establish a comprehensive theoretical framework encompassing core mechanisms such as iron overload and system xc-/GSH/GPX4 imbalance, along with multiple auxiliary pathways. On this basis, we innovatively link ferroptosis with various types of heart failure, covering classic heart failure types and extending our research to pre-heart failure conditions such as arrhythmia and aortic aneurysm, providing new insights for early intervention in heart failure. Importantly, this article systematically integrates multiple strategies of natural products for interfering with ferroptosis, ranging from monomeric compounds and bioactive components to crude extracts and further to traditional Chinese medicine formulae. In addition, non-pharmacological means such as acupuncture are also included.

This study fills the gap in the systematic description of the relationship between ferroptosis and heart failure and the therapeutic strategies of natural products, aiming to provide patients with more diverse treatment options and promote the development of the heart failure treatment field.

The occurrence of necrosis during Mycobacterium bovis (M. bovis) infection is regarded as harmful to the host because it promotes the spread of M. bovis. Ferroptosis is a controlled type of cell death that occurs when there is an excessive buildup of both free iron and harmful lipid peroxides. Here, we demonstrate that the mammalian cell entry (Mce) 4 family protein Mb3523c triggers ferroptosis to promote M. bovis pathogenicity and dissemination. Mechanistically, Mb3523c, through its Y237 and G241 site, interacts with host HSP90 protein to stabilize the LAMP2A on the lysosome to promote the chaperone-mediated autophagy (CMA) pathway. Then, GPX4 is delivered to lysosomes for destruction via the CMA pathway, eventually inducing ferroptosis to promote M. bovis transmission. In summary, our findings offer novel insights into the molecular mechanisms of pathogen-induced ferroptosis, demonstrating that targeting the GPX4-dependent ferroptosis through blocking the M. bovis Mb3523c-host HSP90 interface represents a potential therapeutic strategy for tuberculosis (TB).Abbreviations: CFU: colony-forming units; CMA: chaperone-mediated autophagy; Co-IP: co-immunoprecipitation; Fer-1: ferrostatin-1; GPX4: glutathione peroxidase 4; HSP90: heat shock protein 90; LDH: lactate dehydrogenase; Mce: mammalian cell entry; MOI: multiplicity of infection; Nec-1: necrostatin-1; PI: propidium iodide; RCD: regulated cell death.

Salmonella is one of the most common zoonotic pathogens, posing a significant threat to both animal and human health. Our previous study demonstrated that autophagy plays a crucial role in restricting the intracellular growth of Salmonella. This study aims to investigate the effect of autophagy in Salmonella Typhimurium (S. Typhimurium)-induced ferroptosis. First, we found that S. Typhimurium induced lipid peroxidation by increasing intracellular Fe2 + levels, promoting lipid oxidation, and inhibiting the antioxidant pathway. S. Typhimurium-induced lipid peroxidation led to ferroptosis in macrophages. Further results revealed that S. Typhimurium triggered ferritin degradation by NCOA4-mediated ferritinophagy. Additionally, S. Typhimurium-induced chaperone-mediated autophagy (CMA) degraded GPX4 through TAK1-HSC70 signaling pathway. Notably, GPX4 is involved in intracellular S. Typhimurium release. Overall, autophagy was essential for S. Typhimurium induced-ferroptosis, TAK1 not only facilitated autophagy to eliminate intracellular bacteria but also promoted bacterial release.

Heme, an iron containing organic ring, is required for a diverse range of biological processes across all forms of life. Although this nutrient is essential, its pro-inflammatory and cytotoxic properties can lead to cellular damage. Heme oxygenase 1 (HO-1) is an endoplasmic reticulum (ER)-anchored enzyme that degrades heme, releasing equimolar amounts of carbon monoxide (CO), biliverdin (BV), and iron. The induction of HO-1 by heme presents an interesting dichotomy in the cell: CO and BV possess anti-inflammatory and antioxidant properties while free iron can be detrimental as it can generate hydroxyl radicals through the Fenton reaction. The heme/HO-1 axis is tightly regulated, and can influence cell fate, local tissue environments, and disease outcomes during pathogen infection. In this review we explore the role of heme during macrophage polarization and its ability to act as an immune activator while also examining the contribution of HO-1 and heme during infections with intracellular and extracellular pathogens. We highlight work from the emerging field of nutritional immunity of heme and iron, and how the substrates and byproducts of heme metabolism via HO-1 can be beneficial to the host or the pathogen depending on the context.

Periodontitis is an oral immunoinflammatory disease induced by bacterial infection. During periodontitis, the aggravating destruction of the alveolar bone can result in tooth movement and even tooth loss. Current conventional treatments for periodontitis primarily focus on infection control, but their effectiveness in halting and restoring alveolar bone destruction is limited. To identify additional therapeutic targets, researchers have been dedicated to investigating other pathological mechanisms underlying alveolar bone loss during periodontitis. Recently, findings indicate that ferroptosis plays a role in the development of periodontitis. Ferroptosis is a nonapoptotic type of cell death marked by iron accumulation and lipid peroxidation. Recent investigations have revealed the complex interplay of ferroptosis and inflammation. The positive feedback loop between ferroptosis and inflammation may significantly contribute to the exacerbation of alveolar bone loss. In light of the advancements in research within this field in recent years, this review intends to thoroughly summarize the processes by which ferroptosis aggravates alveolar bone loss during periodontitis, along with relevant ferroptosis-targeted therapeutic agents. By highlighting the latest advancements in this area, we hope this review will inspire researchers to develop novel therapeutic strategies for more effective inflammation control and regeneration of alveolar bone.

Otitis media (OM) is a disease involving inflammation and infection of the middle ear that primarily affects children. Fos-like antigen 1 (FOSL1), a component of AP1 transcription factor complexes, is a key regulator in inflammation and various diseases. However, the role of FOSL1 in OM remains largely unknown. Our study aimed to elucidate the function and mechanism of FOSL1 in OM.

The gene expression dataset was obtained from Gene Expression Omnibus (GEO), and the differentially expressed genes (DEGs) from OM mice and control mice were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were used to identify potential biological pathways. Gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA) were performed to excavate the biological signaling pathways. The OM cell model was induced by Staphylococcus aureus and Bacillus cereus administration. The expression of FOSL1 and ferroptosis-related proteins in OM cell model were determined by western blot. Inflammatory cytokines in cells were detected by qPCR.

DEGs was identified from gene set enrichment (GSE) 49128, 441 genes were up-regulated and 180 were down-regulated. FOSL1 was highly expressed in OM mice. Consistent with the bioinformatic analysis, the expression of FOSL1 in bacterial-induced OM cells was upregulated. Inhibition of FOSL1 via siRNA alleviated the inflammatory response and cell ferroptosis in the OM cell model. The reduced level of inflammatory cytokines and cell ferroptosis induced by FOSL1 inhibition could be rescued by ferroptosis activator erastin.

FOSL1 inhibition could alleviate release of inflammatory cytokines and ferroptosis in the OM cell model.

The ferroptosis of cardiomyocytes has been recognized as the core pathological mechanism of heart failure. During the evolution of cardiovascular diseases, the accumulation of angiotensin II and advanced glycation end products can lead to the excessive activation of the RAGE/TLR4-JNK1/2 pathway, which subsequently triggers ferritinophagy, clockophagy, and enhanced p53 activity, ultimately leading to cardiomyocyte ferroptosis. It is evident that deeply unraveling the specific mechanisms in this field and comprehensively evaluating potential drugs and therapeutic strategies targeting this pathway is crucial for improving the status of cardiomyocyte ferroptosis. However, our current understanding of this pathway's specific molecular biological mechanisms in the process of cardiomyocyte ferroptosis remains limited. In light of this, this paper first comprehensively reviews the historical context of ferroptosis research, compares the similarities and differences between ferroptosis and other standard modes of cell death, elucidates the core mechanisms of ferroptosis and its close connection with heart failure, aiming to establish a basic cognitive framework for readers on ferroptosis and its role in heart failure. Subsequently, the paper delves into the pivotal role of the RAGE/TLR4-JNK1/2 pathway in cardiomyocyte ferroptosis and its intricate molecular biological regulatory network. Furthermore, it systematically integrates various therapeutic approaches aimed at inhibiting RAGE, TLR4, and JNK1/2 activity to alleviate cardiomyocyte ferroptosis, encompassing RNA interference technology, gene knockout techniques, small molecule inhibitors, natural active ingredients, as well as traditional Chinese and Western medicines, with the ultimate goal of forging new avenues and strategies for the prevention and treatment of heart failure.

A quarter of human population is infected with Mycobacterium tuberculosis, but less than 10% of those infected develop pulmonary TB. We developed a genetically defined sst1-susceptible mouse model that uniquely reproduces a defining feature of human TB: the development of necrotic lung granulomas and determined that the sst1-susceptible phenotype was driven by the aberrant macrophage activation. This study demonstrates that the aberrant response of the sst1-susceptible macrophages to prolonged stimulation with TNF is primarily driven by conflicting Myc and antioxidant response pathways leading to a coordinated failure 1) to properly sequester intracellular iron and 2) to activate ferroptosis inhibitor enzymes. Consequently, iron-mediated lipid peroxidation fueled Ifn-beta superinduction and sustained the Type I Interferon (IFN-I) pathway hyperactivity that locked the sst1-susceptible macrophages in a state of unresolving stress and compromised their resistance to Mtb. The accumulation of the aberrantly activated, stressed, macrophages within granuloma microenvironment led to the local failure of anti-tuberculosis immunity and tissue necrosis. The upregulation of Myc pathway in peripheral blood cells of human TB patients was significantly associated with poor outcomes of TB treatment. Thus, Myc dysregulation in activated macrophages results in an aberrant macrophage activation and represents a novel target for host-directed TB therapies.

Macrophages are the primary host cell type for infection by Mycobacterium tuberculosis in vivo. Macrophages are also key immune effector cells that mediate the control of bacterial growth. However, the specific macrophage phenotypes that are required for optimal immune control of M. tuberculosis infection in vivo remain poorly defined. There are two distinct macrophage lineages in the lung, comprising embryonically derived, tissue-resident alveolar macrophages and recruited, blood monocyte-derived interstitial macrophages. Recent studies have shown that these lineages respond divergently to similar immune environments within the tuberculosis granuloma. Here, we discuss how the differing responses of macrophage lineages might affect the control or progression of tuberculosis disease. We suggest that the ability to reprogramme macrophage responses appropriately, through immunological or chemotherapeutic routes, could help to optimize vaccines and drug regimens for tuberculosis.

Sepsis-induced cardiomyopathy is a reversible non-ischemic acute cardiac dysfunction associated with sepsis. It is strongly associated with an abnormal immune response. It emerges as a vital threat to public health owing to its high mortality rate. However, the exact pathogenesis requires further investigation. In recent years, NETosis and ferroptosis, which are novel modes of programmed cell death, have been identified and found to play important roles in sepsis-related organ damage. This article outlines the mechanisms of these two modes of cell death, discusses the role of neutrophil extracellular traps in myocardial injury and the importance of ferroptosis in sepsis-induced cardiomyopathy, and reviews the potential interconnection between these two types of programmed cell death in sepsis-induced cardiomyopathy.

Glaesserella parasuis cytolethal distending toxin (GpCDT) is a bacterial genotoxin whose main action is to activate DNA damage responses, induce cell cycle arrest, and induce the apoptosis of host cells. In our previous studies, we reported that cells incubated with GpCDT exhibited changes in the expression of ferroptosis-related proteins; thus, we hypothesized that, in addition to apoptosis, GpCDT may also cause ferroptosis, a novel mode of cell death. Here, we observed that treatment of 3D4/21 cells with GpCDT resulted in cytoplasmic iron overload, depletion of GSH (reduced glutathione), and overproduction of reactive oxygen species (ROS) and malondialdehyde (MDA), indicating that GpCDT disrupted iron metabolism and redox homeostasis in these cells. These phenomena were counteracted by the specific ferroptosis inhibitor ferrostatin-1 and the iron chelator deferoxamine mesylate. In vitro infection with the Glaesserella parasuis field isolate strain SC1401 (CDT positive) induced changes in the expression of ferroptosis biomarkers and proteins. Infection of C57BL/6 mice yielded similar results. Our results suggest that ferroptosis may play a substantial role in GpCDT-induced cellular injury.

Chlamydia trachomatis, the most prevalent bacterial agent of sexually transmitted infections, poses a significant threat to reproductive health. The release of progeny through the orchestrated lysis of host cells plays a crucial role for the development of new infections, though the underlying molecular mechanisms remaining largely unexplored. In this study, we identified a novel mechanism by which Chlamydia induces host cell ferroptosis to facilitate its progeny release. This process involves the degradation of the host protein SLC7A11 by the chlamydial protease-like activity factor (CPAF), resulting in glutathione depletion and subsequent cell death characterized by lipid peroxidation. Infection with a CPAF-deficient strain fails to induce host cell ferroptosis. Notably, inhibiting ferroptosis by vitamin E reduces the Chlamydia burden in low genital tract of mice and trends toward attenuation of pathology. These findings provide new insights into the conserved survival strategies of Chlamydia and understanding of its pathogenesis.

We present here a comprehensive update on recent advancements in the field of ferroptosis, with a particular emphasis on its metabolic underpinnings and physiological impacts. After briefly introducing landmark studies that have helped to shape the concept of ferroptosis as a distinct form of cell death, we critically evaluate the key metabolic determinants involved in its regulation. These include the metabolism of essential trace elements such as selenium and iron; amino acids such as cyst(e)ine, methionine, glutamine/glutamate, and tryptophan; and carbohydrates, covering glycolysis, the citric acid cycle, the electron transport chain, and the pentose phosphate pathway. We also delve into the mevalonate pathway and subsequent cholesterol biosynthesis, including intermediate metabolites like dimethylallyl pyrophosphate, squalene, coenzyme Q (CoQ), vitamin K, and 7-dehydrocholesterol, as well as fatty acid and phospholipid metabolism, including the biosynthesis and remodeling of ester and ether phospholipids and lipid peroxidation. Next, we highlight major ferroptosis surveillance systems, specifically the cyst(e)ine/glutathione/glutathione peroxidase 4 axis, the NAD(P)H/ferroptosis suppressor protein 1/CoQ/vitamin K system, and the guanosine triphosphate cyclohydrolase 1/tetrahydrobiopterin/dihydrofolate reductase axis. We also discuss other potential anti- and proferroptotic systems, including glutathione S-transferase P1, peroxiredoxin 6, dihydroorotate dehydrogenase, glycerol-3-phosphate dehydrogenase 2, vitamin K epoxide reductase complex subunit 1 like 1, nitric oxide, and acyl-CoA synthetase long-chain family member 4. Finally, we explore ferroptosis's physiological roles in aging, tumor suppression, and infection control, its pathological implications in tissue ischemia-reperfusion injury and neurodegeneration, and its potential therapeutic applications in cancer treatment. Existing drugs and compounds that may regulate ferroptosis in vivo are enumerated.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains one of the leading causes of death worldwide. TB pathogenesis is shaped by a complex interaction between the pathogen and host immune responses, particularly through mechanisms such as oxidative stress and ferroptosis; a form of regulated necrotic cell death driven by iron-dependent lipid peroxidation. This Review highlights recent insights into how Mtb modulates oxidative stress pathways and thus triggers ferroptosis in host cells. Understanding the interplay between oxidative stress responses and cellular and tissue necrosis opens new avenues for therapeutic interventions of TB by controlling bacterial growth and preventing host tissue damage.

In murine models of visceral leishmaniasis (VL), the parasitization of resident Kupffer cells (resKCs) drives early Leishmania infantum growth in the liver, leading to granuloma formation and subsequent parasite control. Using the chronic VL model, we demonstrate that polyclonal resKCs redistributed to form granulomas outside the sinusoids, creating an open sinusoidal niche that was gradually repopulated by monocyte-derived KCs (moKCs) acquiring a tissue specific, homeostatic profile. Early-stage granulomas predominantly consisted of CLEC4F+KCs. In contrast, late-stage granulomas led to remodeling of the sinusoidal network and contained monocyte-derived macrophages (momacs) along with KCs that downregulated CLEC4F, with both populations expressing iNOS and pro-inflammatory chemokines. During late-stage infection, parasites were largely confined to CLEC4F-KCs. Reduced monocyte recruitment and increased resKCs proliferation in infected Ccr2-/- mice impaired parasite control. These findings show that the ontogenic heterogeneity of granuloma macrophages is closely linked to granuloma maturation and the development of hepatic immunity in VL.

Respiratory infectious diseases, particularly those caused by respiratory viruses, have the potential to lead to global pandemics, thereby posing significant threats to public and human health. Historically, the primary treatment for respiratory bacterial infections has been antibiotic therapy, while severe cases of respiratory viral infections have predominantly been managed by controlling inflammatory cytokine storms. Ferroptosis is a novel form of programmed cell death that is distinct from apoptosis and autophagy. In recent years, Recent studies have demonstrated that ferroptosis plays a significant regulatory role in various respiratory infectious diseases, indicating that targeting ferroptosis may represent a novel approach for the treatment of these conditions. This article summarized the toxic mechanisms underlying ferroptosis, its relationship with respiratory infectious diseases, the mechanisms of action, and current treatment strategies. Particular attentions were given to the interplay between ferroptosis and Mycobacterium tuberculosis, Epstein-Barr virus, severe acute respiratory syndrome coronavirus-2, Pseudomonas aeruginosa, dengue virus, influenza virus and herpes simplex virus type1infection. A deeper understanding of the regulatory mechanisms of ferroptosis in respiratory infections will not only advance our knowledge of infection-related pathophysiology but also provide a theoretical foundation for the development of novel therapeutic strategies. Targeting ferroptosis pathways represents a promising therapeutic approach for respiratory infections, with significant clinical and translational implications.

Immune suppression heightens the risk for fungal infections, but the mechanisms that result in clinical disease are poorly understood. Here we demonstrate that macrophage ferroptosis, an iron-dependent form of regulated cell death, inhibits Aspergillus fumigatus ( Af ) killing. In a mouse tracheal transplant model of Af infection, we observed an increase in macrophage lipid peroxidation, a decreased expression of negative ferroptosis regulators Gpx4 and Slc7a11 , and an increase in positive regulators Ptgs2 and Nox2 , relative to syntransplants. Depletion of macrophages in transplant recipients decreased Af invasion. In vitro , iron overload reduced macrophage viability and decreased their capability to kill Af spores, through a decrease in lysosomal acidification and lysosomal loss. Treatment with ferrostatin-1, a ferroptosis inhibitor, and deferasirox (an iron chelator) restored Af killing. Ferroptotic alveolar macrophages isolated from lung transplant patients also showed a decreased ability to kill Af spores and the patients' bronchoalveolar lavage was characterized by higher iron levels and markers of ferroptotic stress compared to non-lung transplants. These characteristics were strongly correlated with a clinical history of fungal infections, independent of immune suppressive medications. Our findings indicate that macrophage ferroptosis augments the risk of invasive aspergillosis, representing a novel mechanism for host immune dysfunction.

In the gastro-intestinal tract, Escherichia coli (E.coli) infections can trigger programmed cell death of intestinal epithelial cells, through mechanisms such as oxidative stress and ferroptosis, which compromise gut barrier integrity. Given the rising prevalence of antibiotic-resistant E. coli strains, there is an urgent need to develop innovative antimicrobial therapies that go beyond conventional antibiotics. Antimicrobial peptides represent a promising alternative for combating resistant bacterial strains due to their dual role in antimicrobial activity and immune modulation. In this study, we constructed multiple expression cassettes to express porcine β-defensin 2 (PBD2)-derived peptide RH in Pichia pastoris (P. pastoris), purified the peptide using nickel column affinity chromatography, and assessed its in vivo and in vitro activity. The results indicated that under the optimal condition (3% methanol), the total secreted protein concentration reached 306.5 mg/L after 120 h of fermentation. Following purification, the yield of recombinant active peptide RH (rRH) can reached 59.34 mg/L. The rRH exhibits strong antimicrobial activity and resistance to oxidation, and by inhibiting oxidative stress-mediated ferroptosis it reduces E. coli-induced cell death and injury in the jejunum. This dual functionality of rRH positions it as a potential therapeutic candidate for treating gastrointestinal infections and improving gut health, providing a crucial alternative to traditional antibiotics.

The genetic and molecular determinants that underlie the heterogeneity of Mycobacterium tuberculosis (Mtb) infection outcomes in humans are poorly understood. Multiple lines of evidence demonstrate that mitochondrial dysfunction can exacerbate mycobacterial disease severity, and mutations in some mitochondrial genes confer susceptibility to mycobacterial infection in humans. Here, we report that mutations in mitochondria DNA (mtDNA) polymerase gamma potentiate susceptibility to Mtb infection in mice. PolgD257A mutator mtDNA mice fail to mount a protective innate immune response at an early infection time point, evidenced by high bacterial burdens, reduced M1 macrophages, and excessive neutrophil infiltration in the lungs. Immunohistochemistry reveals signs of enhanced necrosis in the lungs of Mtb-infected PolgD257A mice, and PolgD257A mutator macrophages are hypersusceptible to extrinsic triggers of necroptosis ex vivo. By assigning a role for mtDNA mutations in driving necrosis during Mtb infection, this work further highlights the requirement for mitochondrial homeostasis in mounting balanced immune responses to Mtb.

Staphylococcus aureus-induced mastitis is a significant cause of economic losses in the dairy industry, yet its molecular mechanisms remain poorly defined. Although ferroptosis, a regulated cell death process, is associated with inflammatory diseases, its role in bovine mastitis is unknown. In this study, 11 S. aureus strains were isolated from milk samples obtained from cows with clinical or subclinical mastitis. Transcriptome analysis of Mac-T cells challenged with isolated S. aureus identified differentially expressed genes (DEGs). Enrichment analysis revealed significant associations between DEG clusters and traits related to bovine mastitis. KEGG pathway enrichment revealed ferroptosis, Toll-like receptor, and TNF signaling as significantly enriched pathways. Weighted gene co-expression network analysis (WGCNA) further prioritized ferroptosis-related genes (HMOX1, SLC11A2, STEAP3, SAT1, and VDAC2) involved in iron metabolism. Notably, the expression levels of HMOX1 and SAT1 were significantly increased in S. aureus-challenged Mac-T cells, and this upregulation was consistent with trends observed in transcriptome data from mother-daughter pairs of cows with subclinical mastitis caused by S. aureus infection. Furthermore, Ferrostatin-1 treatment significantly reduced the expression of HMOX1 and SAT1 in S. aureus-challenged cells, confirming the involvement of ferroptosis in this process. This study reveals that ferroptosis plays a key role in S. aureus-induced mastitis and highlights its potential as a target for molecular breeding strategies aimed at improving bovine mastitis resistance.

Ferroptosis is a distinct form of iron-dependent programmed cell death characterized primarily by intracellular iron accumulation and lipid peroxidation. Multiple cellular processes, including amino acid metabolism, iron metabolism, lipid metabolism, various signaling pathways, and autophagy, have been demonstrated to influence the induction and progression of ferroptosis. Recent investigations have elucidated that ferroptosis plays a crucial role in the pathogenesis of various pulmonary disorders, including lung injury, chronic obstructive pulmonary disease, pulmonary fibrosis, and asthma. Ferroptosis is increasingly recognized as a promising novel strategy for cancer treatment. Various immune cells within the tumor microenvironment, including CD8+ T cells, macrophages, regulatory T cells, natural killer cells, and dendritic cells, have been shown to induce ferroptosis in tumor cells and modulate the process through the regulation of iron and lipid metabolism pathways. Conversely, ferroptosis can reciprocally alter the metabolic environment, leading to the activation or inhibition of immune cell functions, thereby modulating immune responses. This paper reviews the molecular mechanism of ferroptosis and describes the tumor immune microenvironment, discusses the connection between ferroptosis and the tumor microenvironment in lung cancer and pulmonary diseases, and discusses the development prospect of their interaction in the treatment of lung cancer and pulmonary diseases.

Sepsis is a life-threatening disease causing millions of deaths every year. It has been reported that programmed cell death (PCD) plays a critical role in the development and progression of sepsis, which has the potential to be a diagnosis and prognosis indicator for patient with sepsis.

Fourteen PCD patterns were analyzed for model construction. Seven transcriptome datasets and a single cell sequencing dataset were collected from the Gene Expression Omnibus database.

A total of 289 PCD-related differentially expressed genes were identified between sepsis patients and healthy individuals. The machine learning algorithm screened three PCD-related genes, NLRC4, TXN and S100A9, as potential biomarkers for sepsis. The area under curve of the diagnostic model reached 100.0% in the training set and 100.0%, 99.9%, 98.9%, 99.5% and 98.6% in five validation sets. Furthermore, we verified the diagnostic genes in sepsis patients from our center via qPCR experiment. Single cell sequencing analysis revealed that NLRC4, TXN and S100A9 were mainly expressed on myeloid/monocytes and dendritic cells. Immune infiltration analysis revealed that multiple immune cells involved in the development of sepsis. Correlation and gene set enrichment analysis (GSEA) analysis revealed that the three biomarkers were significantly associated with immune cells infiltration.

We developed and validated a diagnostic model for sepsis based on three PCD-related genes. Our study might provide potential peripheral blood diagnostic candidate biomarkers for patients with sepsis.

Crosstalk between cell death programs confers appropriate host anti-infection immune responses, but how pathogens co-opt host molecular switches of cell death pathways to reprogram cell death modalities for facilitating infection remains largely unexplored. Here, we identify mammalian cell entry 3C (Mce3C) as a pathogenic cell death regulator secreted by Mycobacterium tuberculosis (Mtb), which causes tuberculosis featured with lung inflammation and necrosis. Mce3C binds host cathepsin B (CTSB), a noncaspase protease acting as a lysosome-derived molecular determinant of cell death modalities, to inhibit its protease activity toward BH3-interacting domain death agonist (BID) and receptor-interacting protein kinase 1 (RIPK1), thereby preventing the production of proapoptotic truncated BID (tBID) while maintaining the abundance of pronecroptotic RIPK1. Disrupting the Mce3C-CTSB interaction promotes host apoptosis while suppressing necroptosis with attenuated Mtb survival and mitigated lung immunopathology in mice. Thus, pathogens manipulate host lysosomal protease activity-dependent plasticity in cell death modalities to promote infection and pathogenicity.

Tuberculosis, induced by Mycobacterium tuberculosis (Mtb), continues to pose a significant global public health challenge. Ferroptosis has emerged as a pivotal factor in tuberculosis pathogenesis, however, the mechanism has not yet been fully clarified. Therefore, the aim of this study was to hypothesize and validate potential ferroptosis-related genes in Mtb infection through bioinformatics analysis, thereby offering insights for further investigation. The mRNA microarray expression profile datasets were sourced from the Gene Expression Omnibus. The differentially expressed genes (DEGs) were derived using GEO2R. Subsequently, the shared DEGs between the GSE174566 and GSE227851 datasets were intersected with the genes in the ferroptosis database. The ferroptosis-associated shared DEGs (Ferr-sDEGs) were validated in the GSE20050 dataset. They were subjected to PPI, Cytoscape and Friends analysis, the infiltration correlation of immune cells and qRT-PCR. A total of 11 Ferr-sDEGs were identified, and 9 genes were validated. These analyses revealed that the key Ferr-sDEGs contributed to ferroptosis during Mtb infection and these key Ferr-sDEGs were relatively independent, implying that ferroptosis may be triggered by various mechanisms. Concurrently, the infiltration and correlation analysis demonstrated that multiple types of immune cells could be activated by the key Ferr-sDEGs. Ultimately, qRT-PCR validated that the expression levels of key Ferr-sDEGs. In conclusion, ferroptosis serves a pivotal function in the pathogenesis of tuberculosis. IL1B, PTGS2, TNFAIP3, HMOX1, SOCS1, CD82, and NUPR1 may be vital genes associated with the ferroptosis induced by Mtb infection.

Sepsis associated acute lung injury (SALI) is a common complication in patients with severe sepsis and a disease with high morbidity and mortality in ICU patients. The main mechanism of SALI is pulmonary hypoperfusion due to hypotension and shock caused by sepsis, which leads to ischemic necrosis of alveolar endothelial cells and eventually lung failure. At present, SALI therapy mainly includes antibiotic therapy, fluid resuscitation, transfusion products and vasoactive drugs, but these strategies are not satisfactory. Therefore, focusing on the role of different cell death patterns in SALI may help in the search for effective treatments. Understanding the molecular mechanisms of SALI and identifying pathways that inhibit lung cell death are critical to developing effective drug therapies to prevent the progression of SALI. Cell death is controlled by programmed cell death (PCD) pathways, including apoptosis, necroptosis, ferroptosis, pyroptosis and autophagy. There is growing evidence that PCD plays an important role in the pathogenesis of SALI, and inhibitors of various types of PCD represent a promising therapeutic strategy. Therefore, understanding the role and mechanism of PCD in SALI is conducive to our understanding of its pathological mechanism, and is of great significance for the treatment of SALI. In this article, we discuss recent advances in the role of PCD in SALI, show how different signaling pathways (such as NF-κB, PI3K/Akt, mTOR, and Nrf2) regulate PCD to regulate SALI development, and discuss the associations between various types of PCD. The aim is to explore the molecular mechanism behind SALI and to find new targets for SALI therapy.

In tuberculosis (TB) infection, monocytes play a crucial role in regulating the balance between immune tolerance and immune response through various mechanisms. A deeper understanding of the roles of monocyte subsets in TB immune responses may facilitate the development of novel immunotherapeutic strategies and improve TB prevention and treatment.

We retrieved and processed raw single-cell RNA-seq data from SRP247583. Single-cell RNA-seq combined with bioinformatics analysis was employed to investigate the roles of monocytes in TB progression.

Our findings revealed that classical monocytes expressing inflammatory mediators increased as the disease progressed, whereas non-classical monocytes expressing molecules associated with anti-pathogen infection were progressively depleted. Pseudotime analysis delineated the differentiation trajectory of monocytes from classical to intermediate to non-classical subsets. An abnormal differentiation trajectory to non-classical monocytes may represent a key mechanism underlying TB pathogenesis, with CEBPB and CORO1A identified as genes potentially related to TB development. Analysis of key transcription factors in non-classical monocytes indicated that IRF9 was the only downregulated transcription factor with high AUC activity in this subset. The expression of IRF9 exhibited a decreasing trend in both latent TB infection (LTBI) and active TB groups. Furthermore, dysregulation of transcription factor regulatory networks appeared to impair ferroptosis, with ferroptosis-associated genes MEF2C, MICU1, and PRR5 identified as potential targets of IRF9. Through cell communication analysis, we found that interactions between non-classical monocytes and other subpopulations may mediate TB progression, with MIF and LGALS9 highlighted as potential signaling pathways.

This study employs bioinformatics analysis in conjunction with single-cell sequencing technology to uncover the crucial role of monocyte subsets in tuberculosis infection.

Ferroptosis is a unique form of regulated cell death that results from unrestricted lipid peroxidation, and it enhances the production of intracellular oxidative stress molecules. In this study, we investigated the effect of macrophage ferroptosis on the proliferation of Staphylococcus aureus (S. aureus) and sought potential host-directed therapy (HDT) targets for S. aureus. The study findings revealed that erastin concentrations (< 20 μM), which do not have an impact on macrophage proliferation, can effectively impede the proliferation of S. aureus within macrophages. High-throughput sequencing was used to identify DEGs and DEMIs in infected macrophages. Subsequently, the mRNA-miRNA regulatory network was successfully constructed, and two sets of molecules were selected. Experimental findings confirmed that mmu-miR-6935-5p exhibited complementary binding to specific sequences within the GM867 mRNA, and mmu-miR-7082-3p specifically bound to the GPR176 mRNA. Inducing ferroptosis in macrophages can effectively impede the proliferation of drug-resistant S. aureus. Notably, our study has identified GM867, GPR176, mmu-miR-6935-5p, and mmu-miR-7082-3p as key regulators involved in this process. These findings highlight the potential of targeting these four molecules for HDT, offering novel ways to combat drug-resistant S. aureus infection.

Tuberculosis (TB) caused by Mycobacterium tuberculosis (M.tb) remains a global health crisis, with over 10 million people affected annually. Despite advancements in treatment, M.tb has developed mechanisms to evade host immune responses, complicating efforts to eradicate the disease. Two emerging cell death pathways, ferroptosis and cuproptosis, have been linked to TB pathogenesis. Ferroptosis, an iron-dependent form of cell death, is driven by lipid peroxidation and reactive oxygen species (ROS) accumulation. This process can limit M.tb replication by depleting intracellular iron and inducing macrophage necrosis. However, excessive ferroptosis may lead to tissue damage and aid bacterial dissemination. Cuproptosis, triggered by copper accumulation, disrupts mitochondrial metabolism, leading to protein aggregation and cell death. M.tb exploits both iron and copper metabolism to survive within macrophages, manipulating these processes to resist oxidative stress and immune responses. This review examines the roles of ferroptosis and cuproptosis in TB, discussing how M.tb manipulates these pathways for survival. While therapeutic strategies targeting these processes, such as ferroptosis inducers (Erastin, RSL3) and inhibitors (Ferrostatin-1) and copper ionophores (Disulfiram, Elesclomol) and chelators, show promise, the limited understanding of these pathways and potential off-target effects remains a significant challenge. Further exploration of these pathways may provide insights into the development of targeted therapies aimed at controlling M.tb infection while minimizing host tissue damage. By elucidating the complex interactions between ferroptosis, cuproptosis, and TB, future therapies could better address bacterial resistance and improve clinical outcomes.

Copper, as a vital trace element and ubiquitous environmental pollutant, exhibits a positive correlation with the neurodegenerative diseases. Recent studies have highlighted ferroptosis's significance in heavy metal-induced neurodegenerative diseases, yet its role in copper-related neurotoxicity remains unclear. This study aimed to investigate the role of ferroptosis in copper-induced neurotoxicity. Previously, we established that copper induced motor behaviors inhibition and neuronal degeneration through oxidative stress in Caenorhabditis elegans (C. elegans). This study revealed that the behavior inhibition (head thrash, body bends, pumping frequency and defecation interval) and neuronal degeneration (GABAergic neurons and dopaminergic neurons) in copper-treated nematodes were reversed by the ferroptosis inhibitor Fer-1. Additionally, copper treatment increased the Fe2+ level and MDA content, and decreased GSH content, suggesting copper activated the ferroptosis in C. elegans. Furthermore, studies found that copper exposure altered the expression of ferroptosis-related genes gpx-1, ftn-1, and acs-17 in C. elegans. The results showed RNAi of gpx-1 and RNAi of ftn-1 significantly promoted Cu-induced neurotoxicity, while the RNAi of acs-17 appeared to rescue the Cu-induced ferroptosis and neurotoxicity. In conclusion, Cu might induce behavior inhibition and neuronal degeneration through ferroptosis in C. elegans. The findings of this study provided new insights in the mechanisms underlying Cu-induced neurotoxicity.

As a novel form of cell death, ferroptosis is mainly regulated by the accumulation of soluble iron ions in the cytoplasm and the production of lipid peroxides and is closely associated with several diseases, including acute kidney injury, ischemic reperfusion injury, neurodegenerative diseases, and cancer. The term "immunosuppression" refers to various factors that can directly harm immune cells' structure and function and affect the synthesis, release, and biological activity of immune molecules, leading to the insufficient response of the immune system to antigen production, failure to successfully resist the invasion of foreign pathogens, and even organ damage and metabolic disorders. An immunosuppressive phase commonly occurs in the progression of many ferroptosis-related diseases, and ferroptosis can directly inhibit immune cell function. However, the relationship between ferroptosis and immunosuppression has not yet been published due to their complicated interactions in various diseases. Therefore, this review deeply discusses the contribution of ferroptosis to immunosuppression in specific cases. In addition to offering new therapeutic targets for ferroptosis-related diseases, the findings will help clarify the issues on how ferroptosis contributes to immunosuppression.

Extrapulmonary tuberculosis (EPTB) accounts for approximately 17% of all Mycobacterium tuberculosis (M.tb) infections globally. Immunocompromised individuals, such as those with HIV infection or type 2 diabetes mellitus (T2DM), are at an increased risk for EPTB. Previous studies have demonstrated that patients with HIV and T2DM exhibit diminished synthesis of glutathione (GSH) synthesizing enzymes. In a murine model, we showed that the diethyl maleate (DEM)-induced depletion of GSH in the lungs led to increased M.tb burden and an impaired pulmonary granulomatous response to M.tb infection. However, the effects of GSH depletion during active EPTB in the liver and spleen have yet to be elucidated. In this study, we evaluated hepatic GSH and malondialdehyde (MDA) levels, as well as cytokine profiles, in untreated and DEM-treated M.tb-infected wild-type (WT) C57BL/6 mice. Additionally, we assessed hepatic and splenic M.tb burdens and tissue pathologies. DEM treatment resulted in a significant decrease in the levels of the reduced form of GSH and an increase in MDA, oxidized GSH, and interleukin (IL)-6 levels. Furthermore, DEM-induced GSH decrease was associated with decreased production of IL-12 and IL-17 and elevated production of interferon-gamma (IFN-γ), tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-β. A significant increase in M.tb growth was detected in the liver and spleen in DEM-treated M.tb-infected mice. Large, disorganized lymphocyte infiltrates were detected in the hepatic tissues of DEM-treated mice. Overall, GSH diminishment impaired the granulomatous response to M.tb in the liver and exacerbated M.tb growth in both the liver and spleen. These findings provide critical insights into the immunomodulatory role of GSH in TB pathogenesis and suggest potential therapeutic avenues for the treatment of extrapulmonary M.tb infections.

Herpes simplex virus type I (HSV-1) infection is associated with lung injury; however, no specific treatment is currently available. In this study, we found a significant negative correlation between FcRn levels and the severity of HSV-1-induced lung injury. HSV-1 infection increases the methylation of the FcRn promoter, which suppresses FcRn expression by upregulating DNMT3b expression. Analysis of the FcRn promoter revealed that the -1296- to -919-bp region is the key regulatory region, with the CG site at -967/-966 bp being the critical methylation site. The transcription factor JUN binds to this CG site to increase FcRn transcription; however, its activity was significantly inhibited by DNMT3b overexpression. Moreover, 5-Aza-2 effectively reduced HSV-1-induced lung injury and inhibited ferroptosis. Transcriptomic sequencing revealed that the ferroptosis pathway was highly activated in the lung tissues of FcRn-knockout mice via the p53/SLC7A11 pathway. Furthermore, in vivo and in vivo experiments showed that FcRn knockout aggravated lung epithelial cell inflammation by promoting ferroptosis; however, this effect was reversed by a ferroptosis inhibitor. Thus, HSV-1 infection suppressed FcRn expression through promoter methylation and promoted ferroptosis and lung injury. These findings reveal a novel molecular mechanism underlying viral lung injury and suggest potential therapeutic strategies for targeting FcRn.

Rampant phospholipid peroxidation initiated by iron causes ferroptosis unless this is restrained by cellular defences. Ferroptosis is increasingly implicated in a host of diseases, and unlike other cell death programs the physiological initiation of ferroptosis is conceived to occur not by an endogenous executioner, but by the withdrawal of cellular guardians that otherwise constantly oppose ferroptosis induction. Here, we profile key ferroptotic defence strategies including iron regulation, phospholipid modulation and enzymes and metabolite systems: glutathione reductase (GR), Ferroptosis suppressor protein 1 (FSP1), NAD(P)H Quinone Dehydrogenase 1 (NQO1), Dihydrofolate reductase (DHFR), retinal reductases and retinal dehydrogenases (RDH) and thioredoxin reductases (TR). A common thread uniting all key enzymes and metabolites that combat lipid peroxidation during ferroptosis is a dependence on a key cellular reductant, nicotinamide adenine dinucleotide phosphate (NADPH). We will outline how cells control central carbon metabolism to produce NADPH and necessary precursors to defend against ferroptosis. Subsequently we will discuss evidence for ferroptosis and NADPH dysregulation in different disease contexts including glucose-6-phosphate dehydrogenase deficiency, cancer and neurodegeneration. Finally, we discuss several anti-ferroptosis therapeutic strategies spanning the use of radical trapping agents, iron modulation and glutathione dependent redox support and highlight the current landscape of clinical trials focusing on ferroptosis.

Sepsis remains the leading cause of mortality among Intensive Care Unit (ICU) patients, with its pathogenesis and treatment not yet fully elucidated. Ferroptosis plays a critical role in sepsis, suggesting that ferroptosis-related genes may serve as potential therapeutic targets. This study aims to identify key ferroptosis-related genes in sepsis and explore targeted therapeutics. Through differential expression analysis of the GSE13940 and GSE26440 datasets, heme oxygenase-1 (HO-1) was identified as a hub gene associated with ferroptosis. Additionally, single-cell analysis of the GSE175453 dataset revealed a significant upregulation of HO-1 expression in monocyte lineages during sepsis. The cecal ligation and puncture (CLP) method was employed to induce sepsis in a mouse model, lung and intestinal tissues exhibited typical ferroptosis characteristics, with a significant increase in HO-1 expression. However, treatment with the HO-1 inhibitor zinc protoporphyrin (ZNPP) significantly ameliorated ferroptosis in CLP-induced lung and intestinal tissues, as well as in lipopolysaccharide (LPS)-induced THP-1 cells. Subsequently, molecular docking, surface plasmon resonance (SPR), and microscale thermophoresis (MST) experiments demonstrated that ginsenoside Rb1 specifically targets HO-1, identifying K18A as the key binding residue. Finally, experiments conducted both in vitro and in vivo verified that ginsenoside Rb1 significantly reduces HO-1 expression, inhibits ferroptosis in sepsis-induced lung, and intestinal tissues and THP-1 cells, and improves sepsis-induced pulmonary and intestinal damage. In conclusion, this study identifies HO-1 as a key ferroptosis target in sepsis and suggests ginsenoside Rb1 as a potential novel HO-1 inhibitor for the therapeutic approach of sepsis-induced organ dysfunction.

Ferroptosis is a form of cell death that occurs when there is an excess of reactive oxygen species (ROS), lipid peroxidation, and iron accumulation. The precise regulation of metabolic pathways, including iron, lipid, and amino acid metabolism, is crucial for cell survival. This type of cell death, which is associated with oxidative stress, is controlled by a complex network of signaling molecules and pathways. It is also implicated in various respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), acute lung injury (ALI), lung cancer, pulmonary fibrosis (PF), and the coronavirus disease 2019 (COVID-19). To combat drug resistance, it is important to identify appropriate biological markers and treatment targets, as well as intervene in respiratory disorders to either induce or prevent ferroptosis. The focus is on the role of ferroptosis in the development of respiratory diseases and the potential of targeting ferroptosis for prevention and treatment. The review also explores the interaction between immune cell ferroptosis and inflammatory mediators in respiratory diseases, aiming to provide more effective strategies for managing cellular ferroptosis and respiratory disorders.

Copper is a vital trace element crucial for mediating interactions between Mycobacterium and macrophages. Within these immune cells, copper modulates oxidative stress responses and signaling pathways, enhancing macrophage immune functions and facilitating Mycobacterium clearance. Conversely, copper may promote Mycobacterium escape from macrophages through various mechanisms: inhibiting macrophage activity, diminishing phagocytic and bactericidal capacities, and supporting Mycobacterium survival and proliferation. This paradox has intensified research focus on the regulatory role of copper in immune cell-pathogen interactions. Interactions among metal ions can affect Mycobacterium concentration, distribution, and activity within an organism. In this review, we have elucidated the role of copper in these interactions, focusing on the mechanisms by which this metal influences both the immune defense mechanisms of macrophages and the survival strategies of Mycobacterium. The findings suggest that manipulating copper levels could enhance macrophage bactericidal functions and potentially limit Mycobacterium resistance. Therefore, elucidating the regulatory role of copper is pivotal for advancing our understanding of metal homeostasis in immune cell-pathogen dynamics and TB pathogenesis. Furthermore, we recommend further investigation into the role of copper in TB pathogenesis to advance tuberculosis diagnosis and treatment and gain comprehensive insights into metal homeostasis in infectious disease contexts.

The neurological deficits following traumatic spinal cord injury are associated with severe patient disability and economic consequences. Currently, an increasing number of studies are focusing on the importance of ferroptosis during acute organ injuries. However, the spatial and temporal distribution patterns of ferroptosis during SCI and the details of its role are largely unknown. In this study, in vivo experiments revealed that microglia are in close proximity to macrophages, the major cell type that undergoes ferroptosis following SCI. Furthermore, we found that ferroptotic macrophages aggravate SCI by inducing the proinflammatory properties of microglia. In vitro studies further revealed ferroptotic macrophages increased the expression of IL-1β, IL-6, and IL-23 in microglia. Mechanistically, due to the activation of the NF-κB signaling pathway, the expression of IL-1β and IL-6 was increased. In addition, we established that increased levels of oxidative phosphorylation cause mitochondrial reactive oxygen species generation and unfolded protein response activation and trigger an inflammatory response marked by an increase in IL-23 production. Our findings identified that targeting ferroptosis and IL-23 could be an effective strategy for promoting neurological recovery after SCI.