The CRP-Albumin-Lymphocyte (CALLY) index, a novel inflammatory biomarker combining serum albumin, lymphocyte count, and C-reactive protein (CRP), has been proposed for clinical use. This study aimed to investigate the association between CALLY index and Asthma-COPD Overlap (ACO) in the general US population.

We analyzed data from 6,797 participants aged ≥ 40 years from the 2015-2018 National Health and Nutrition Examination Survey (NHANES). Participants were categorized into quartiles based on natural logarithmic transformed (ln) CALLY index. ACO was defined as self-reported physician-diagnosed asthma and COPD. Logistic regression models were used to examine the association between ln CALLY and ACO, adjusting for potential confounders across three models. Generalized additive models, subgroup analyses, and receiver operating characteristic (ROC) curve analysis were also performed.

The prevalence of ACO across the four CALLY quartiles was 5.56%, 1.89%, 1.54%, and 0.66%. In the fully adjusted model, for each 1-unit increase in ln CALLY, the risk of ACO decreased by 43% (OR = 0.57, 95% CI: 0.44-0.73, P = 0.001). Compared with Q1, the risk of ACO in Q2, Q3, and Q4 was reduced by 63% (OR = 0.37), 66% (OR = 0.34), and 87% (OR = 0.13), respectively (P for trend = 0.003). Generalized additive models showed a non-linear negative relationship (P < 0.001). Subgroup analysis revealed that the association remained consistent across different sexes, age groups, races, smoking status, and disease statuses (arthritis, DM, and hypertension). ROC curve analysis indicated moderate predictive ability of ln CALLY for ACO (AUC = 0.675, 95% CI: 0.636-0.714), with an optimal cutoff value of 8.007 (sensitivity 0.669, specificity 0.598).

Higher CALLY index is independently associated with lower risk of ACO, suggesting its potential value as a biomarker for ACO risk assessment in clinical practice. By integrating inflammation, immune, and nutritional status evaluation, the CALLY index offers a novel perspective for early identification of high-risk individuals in clinical practice.

Asthma is a chronic inflammatory lung disease driven by a complex interplay between innate and adaptive immune components. Among these, innate lymphoid cells (ILCs) and innate-like lymphocytes have emerged as crucial players in shaping the disease phenotype. Within the ILC family, group 2 ILCs (ILC2s), in particular, contribute significantly to type 2 inflammation through their rapid production of cytokines such as IL-5 and IL-13, promoting airway eosinophilia and airway hyperreactivity. On the other hand, innate-like lymphocytes such as invariant natural killer T (iNKT) cells can play either pathogenic or protective roles in asthma, depending on the stimuli and lung microenvironment. Regulatory mechanisms, including cytokine signaling, metabolic and dietary cues, and interactions with other immune cells, play critical roles in modulating their functions. In this review, we highlight current findings on the role of ILCs and innate-like lymphocytes in asthma development and pathogenesis. We also examine the underlying mechanisms regulating their function and their interplay with other immune cells. Finally, we explore current therapies targeting these cells and their effector cytokines for asthma management.

Kaempferol is an active compound found in traditional Chinese medicine epimedium soup, which exhibits potent anti-inflammatory and antioxidant properties. Nevertheless, the mechanism of action in rheumatoid arthritis remains unclear. This study constructed targets protein interaction networks by utilizing the String platform. The analysis of GO function and kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment was performed on key target genes. Target gene validation was conducted through microarray analysis. Molecular docking was employed to evaluate the relationship between kaempferol and various key targets. In vitro experiments were conducted to elucidate kaempferol's mechanism of action on rheumatoid arthritis. Topological analysis of the protein protein interaction (PPI) network identified 10 core targets. Mitogen activated protein kinase 8 (MAPK8), peroxisome proliferator-activated receptor gamma (PPARG), and nuclear factor kappa-B (NF-kB) were all differentially expressed in the microarray dataset and all belonged to the target genes of kaempferol. Furthermore, kaempferol exhibited the highest binding affinity for MAPK8. In vitro cellular experiments demonstrated that kaempferol suppressed autophagy, and ameliorated abnormal proliferation and inflammation in rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) cells by activating the MAPK8/NOD-like receptor protein 3(NLRP3) signaling pathway.

Obesity is closely linked to metabolic dysregulation and chronic inflammation, which significantly impact immune cell functions in adipose tissue. Type 2 innate lymphoid cells (ILC2s) have emerged as key regulators of energy homeostasis, positioning them as promising targets for obesity management. However, the mechanisms governing ILC2 activity and their therapeutic potential in obesity are not fully understood. In this study, we demonstrate that ILC2s in obese adipose tissue exhibit increased PD-1 expression, leading to an exhausted phenotype with diminished cytokine production and proliferation. Elevated osteopontin (OPN) levels in adipose tissue are associated with higher PD-1 expression on ILC2s, while adipocyte-derived PD-L1 interacts with PD-1 to further impair ILC2 functionality. Importantly, blocking PD-1 signaling prevents weight gain and alleviates obesity-related metabolic dysfunctions. In addition, the adoptive transfer of PD-1-deficient ILC2s reduces diabetic phenotypes in obese models. Mechanistically, PD-1 signaling drives metabolic reprogramming in ILC2s, affecting fatty acid uptake and energy metabolism through the downregulation of fatty acid binding protein 5 (FABP5). These results, corroborated by findings in human adipose tissue, suggest a conserved OPN-PD-1 axis. Our study identifies the OPN-PD-1-FABP5 pathway as a crucial regulator of ILC2 function in adipose tissue and presents an emerging immune cell-based therapeutic target for obesity treatment.

Innate lymphoid cells (ILC) have emerged as critical immune effectors with key roles in orchestrating the wider immune response. While ILC are relatively rare cells they are found enriched within discrete microenvironments, predominantly within barrier tissues. An emerging body of evidence implicates complex and multi-layered interactions between cell types, tissue structure and the external environment as key determinants of ILC function within these niches. In this review we will discuss the specific components that constitute ILC-associated microenvironments and consider how they act to determine health and disease. The development of holistic, integrated models of ILC function within complex tissue environments will inform new understanding of the contextual cues and mechanisms that determine the protective versus disease-causing roles of this immune cell family.

Lipids are essential biomolecules playing critical roles in cellular processes, including energy storage, membrane structure, and signaling. This review highlights the chemical tools that have been developed to study the role of lipid metabolism in immune function, focusing on T-cell biology. Fatty acids (FAs), as core lipid components, influence immune responses through structural, signaling, and metabolic roles. Recent studies reveal how specific FAs modulate T-cell activation, proliferation, and function, with implications for regulatory and effector subsets. Emerging tools, such as fluorescence-based lipids and click chemistry, enable precise tracking of lipid uptake and metabolism at the single-cell level, addressing limitations of traditional bulk methods. Advances in metabolomics and proteomics offer further insights into lipid-mediated immune regulation. Understanding these mechanisms provides opportunities to target lipid metabolism in therapeutic strategies for cancer and other immune-related diseases. The integration of lipidomic technologies into immunology uncovers novel perspectives on how lipids shape immune responses at cellular and molecular scales.

Group 2 Innate Lymphoid Cells (ILC2s) have recently been shown to exert key regulatory functions in both innate and adaptive immune response networks that drive the establishment and progression of type 2 immunity. Although mainly tissue resident, ILC2s and their crosstalk within tissue microenvironments influence metabolism at both the local and systemic levels. In turn, the energetic demand and metabolic status within these systems shape the diverse phenotypes and effector functions of ILC2s. Deciphering these metabolic networks in ILC2s is therefore essential in understanding their various roles in health as well as their associated pathophysiologies. Here we detail a framework of experimental approaches to study key immunometabolic states of primary murine ILC2s and link them to unique phenotypes and their corresponding functionality. Utilizing flow cytometry, Single Cell ENergetic metabolism by profilIng Translation inHibition (SCENITH), and the Seahorse platform we provide a framework that allows in-depth analysis of cellular bioenergetic states to determine the immunometabolic wiring of ILC2s. Connecting immunometabolic states and networks to ILC2 phenotypes and effector functions with this method will allow future in-depth studies to assess the potential of novel pharmaceutics in altering ILC2 functionality in clinical settings.

Significant advancements have been made in understanding the cellular and molecular mechanisms of type 2 immunity in allergic diseases such as asthma, allergic rhinitis, chronic rhinosinusitis, eosinophilic esophagitis (EoE), food and drug allergies, and atopic dermatitis (AD). Type 2 immunity has evolved to protect against parasitic diseases and toxins, plays a role in the expulsion of parasites and larvae from inner tissues to the lumen and outside the body, maintains microbe-rich skin and mucosal epithelial barriers and counterbalances the type 1 immune response and its destructive effects. During the development of a type 2 immune response, an innate immune response initiates starting from epithelial cells and innate lymphoid cells (ILCs), including dendritic cells and macrophages, and translates to adaptive T and B-cell immunity, particularly IgE antibody production. Eosinophils, mast cells and basophils have effects on effector functions. Cytokines from ILC2s and CD4+ helper type 2 (Th2) cells, CD8 + T cells, and NK-T cells, along with myeloid cells, including IL-4, IL-5, IL-9, and IL-13, initiate and sustain allergic inflammation via T cell cells, eosinophils, and ILC2s; promote IgE class switching; and open the epithelial barrier. Epithelial cell activation, alarmin release and barrier dysfunction are key in the development of not only allergic diseases but also many other systemic diseases. Recent biologics targeting the pathways and effector functions of IL4/IL13, IL-5, and IgE have shown promising results for almost all ages, although some patients with severe allergic diseases do not respond to these therapies, highlighting the unmet need for a more detailed and personalized approach.

Type 2 immunity represents a unique immune module that provides host protection against macro-parasites and noxious agents such as venoms and toxins. In contrast, maladaptive type 2 immune responses cause allergic diseases. While multiple cell types play important roles in type 2 immunity, recent studies in humans and murine models of chronic allergic diseases have shown that a distinct population of tissue-resident, CD4+ T helper type 2 (Th2) cells play a critical role in chronic allergic inflammation. The rules regulating Th2 cell differentiation have remained less well defined than other T cell subsets, but recent studies have shed new light into the specific mechanisms controlling Th2 cell biology in vivo. Here, we review our current understanding of the checkpoints regulating the development and function of tissue-resident Th2 cells with a focus on chronic allergic diseases. We discuss evidence for a barrier tissue checkpoint in initial Th2 cell priming, including the role of neuropeptides, damage-associated molecular patterns, and dendritic cell macro-clusters. Furthermore, we review the evidence for a second barrier tissue checkpoint that instructs the development of multi-cytokine producing, tissue-resident Th2 cells that orchestrate allergic inflammation. Lastly, we discuss potential approaches to therapeutically target tissue-resident Th2 cells in chronic allergic diseases.

Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) is a multifaced enzyme with a wide spectrum of substrates, from lipids through waxes to retinoids, which makes it an interesting therapeutic target. DGAT1 inhibitors are currently at various stages of preclinical and clinical trials, mostly related to metabolic diseases. Interestingly, in recent years, a growing amount of research has shown the influence of DGAT1 on immune cell metabolism and functions, highlighting its important role during infections and tumorigenesis. In this review, we aim to elucidate the potential immunomodulatory effect of DGAT1 in physiological and pathological conditions.

Recent advances have highlighted the crucial role of metabolic reprogramming in shaping the functions of innate lymphoid cells (ILCs), which are vital for tissue immunity and homeostasis. As tissue-resident cells, ILCs dynamically respond to local environmental cues, with tissue-derived metabolites such as short-chain fatty acids and amino acids directly modulating their effector functions. The metabolic states of ILC subsets-ILC1, ILC2, and ILC3-are closely linked to their ability to produce cytokines, sustain survival, and drive proliferation. This review provides a comprehensive analysis of how key metabolic pathways, including glycolysis, oxidative phosphorylation, and fatty acid oxidation, influence ILC activation and function. Furthermore, we explore the complex interactions between these metabolic pathways and tissue-specific metabolites, which can shape ILC-mediated immune responses in health and disease. Understanding these interactions reveals new insights into the pathogenesis of conditions such as asthma, inflammatory bowel disease, and cancer. A deeper understanding of these mechanisms may not only advance our knowledge of disease pathogenesis but also lead to the development of novel therapeutic strategies targeting metabolic pathways in ILCs to treat tissue-specific immune disorders.

The molecular mechanisms by which worm parasites evade host immunity are incompletely understood. In a mouse model of intestinal helminth infection using Heligmosomoides polygyrus bakeri (Hpb), we show that helminthic glutamate dehydrogenase (heGDH) drives parasite chronicity by suppressing macrophage-mediated host defense. Combining RNA-seq, ChIP-seq, and targeted lipidomics, we identify prostaglandin E2 (PGE2) as a major immune regulatory mechanism of heGDH. The induction of PGE2 and other immunoregulatory factors, including IL-12 family cytokines and indoleamine 2,3-dioxygenase 1, by heGDH required p300-mediated histone acetylation, whereas the enzyme's catalytic activity suppressed the synthesis of type 2-promoting leukotrienes by macrophages via 2-hydroxyglutarate. By contrast, the induction of immunoregulatory factors involved the heGDH N terminus by potentially mediating interactions with cellular targets (CD64 and GPNMB) identified by proteomics. Type 2 cytokines counteracted suppressive effects of heGDH on host defense, indicating that type 2 immunity can limit helminth-driven immune evasion. Thus, helminths harness a ubiquitous metabolic enzyme to epigenetically target type 2 macrophage activation and establish chronicity.

The intricate combination of organic and inorganic compounds found in snake venom includes proteins, peptides, lipids, carbohydrates, nucleotides, and metal ions. These components work together to immobilise and consume prey through processes such as paralysis and hypotension. Proteins, both enzymatic and non-enzymatic, form the primary components of the venom. Based on the effects they produce, venom can be classified as neurotoxic, hemotoxic, and cytotoxic. Studies have shown that, after envenomation, proteins in snake venom also contribute significantly to the induction of inflammatory responses which can either have systemic or localized consequences. This review delves into the mechanisms by which snake venom proteins trigger inflammatory responses, focusing on key families such as phospholipase A2, metalloproteinases, serine proteases, C-type lectins, cysteine-rich secretory proteins, and L-amino acid oxidase. In addition, the role of venom proteins in activating various inflammatory pathways, including the complement system, inflammasomes, and sterile inflammation are also summarized. The available therapeutic options are examined, with a focus on antivenom therapy and its side effects. In general, this review offers a comprehensive understanding of the inflammatory mechanisms that are triggered by snake venom proteins and the side effects of antivenom treatment. All these emphasize the need for effective strategies to mitigate these detrimental effects.

Allergic diseases continue to increase in prevalence across the globe. Decades of research has uncovered the cytokines and transcription factors that are central to the allergic immune response, but only in the last few years have we begun to understand the metabolic requirements of allergic immunity. Here, we discuss the metabolic features of so-called 'type 2' lymphocytes, which are heavily implicated in allergy. We highlight the central role that nuclear receptors, such as peroxisome proliferator-activated receptor gamma, play in type 2 lymphocyte biology and explore the influence of dietary and microbial factors in allergic inflammation. In the future, targeting metabolic checkpoints may offer a meaningful way of treating patients with allergic disorders.

Type 2 immune responses play a crucial role in host defense against parasitic infections but can also promote the development of allergies and asthma. This response is orchestrated primarily by group 2 innate lymphoid cells (ILC2) and helper type 2 (Th2) cells, both of which undergo substantial metabolic reprogramming as they transition from resting to activated states. Understanding these metabolic adaptations not only provides insights into the fundamental biology of ILC2 and Th2 cells but also opens up potential therapeutic avenues for the identification of novel metabolic targets that can extend the current treatment regimens for diseases in which type 2 immune responses play pivotal roles. By integrating recent findings, this review underscores the significance of cellular metabolism in orchestrating immune functions and highlights future directions for research in this evolving field.

Non-alcoholic fatty liver disease (NAFLD) is the predominant metabolic liver disorder and currently lacks effective and safe pharmaceutical interventions. Daphnetin (DA), a natural coumarin derivative with anti-inflammatory and antioxidant activities, is a promising agent for NAFLD treatment. In this study, we evaluated the effects and mechanisms of DA on hepatic lipid metabolism in ob/ob mice. Our results showed that DA effectively ameliorates glucose metabolism and hepatic lipid accumulation in ob/ob mice. Metabolomics and RNA sequencing (RNA-seq), combined with GEO data analysis, suggest that DA primarily modulates the peroxisome proliferator-activated receptor gamma (PPARG) pathway, as validated in vivo in ob/ob mice. Mechanistically, DA selectively targets PPARG in hepatic cells by inhibiting PPARG promoter activity and downregulating its expression, resulting in decreased transcription of downstream lipid metabolism-related genes, including fatty acid binding protein 4 (Fabp4), cluster of differentiation 36 (Cd36), and fatty acid synthase (Fasn). This effect was abolished in PPARG-deficient HepG2 cells subjected to palmitic acid (PA) insult. Our findings provide evidence that DA acts as a selective suppressor of hepatic PPARG, suggesting an attractive strategy by targeting PPARG for the prevention of hepatic steatosis.

Tissue-resident innate immune cells have important functions in both homeostasis and pathological states. Despite advances in the field, analyzing the metabolism of tissue-resident innate lymphocytes is still challenging. The small number of tissue-resident innate lymphocytes such as ILC, NK, iNKT and γδ T cells poses additional obstacles in their metabolic studies. In this review, we summarize the current understanding of innate lymphocyte metabolism and discuss potential pitfalls associated with the current methodology relying predominantly on in vitro cultured cells or bulk-level comparison. Meanwhile, we also summarize and advocate for the development and adoption of single-cell metabolic assays to accurately profile the metabolism of tissue-resident immune cells directly ex vivo.

Lipid droplets (LDs) are crucial for maintaining lipid and energy homeostasis within cells. LDs are highly dynamic organelles that present a phospholipid monolayer rich in neutral lipids. Additionally, LDs are associated with structural and nonstructural proteins, rapidly mobilizing lipids for various biological processes. Lipids play a pivotal role during viral infection, participating during viral membrane fusion, viral replication, and assembly, endocytosis, and exocytosis. SARS-CoV-2 infection often induces LD accumulation, which is used as a source of energy for the replicative process. These findings suggest that LDs are a hallmark of viral infection, including SARS-CoV-2 infection. Moreover, LDs participate in the inflammatory process and cell signaling, activating pathways related to innate immunity and cell death. Accumulating evidence demonstrates that LD induction by SARS-CoV-2 is a highly coordinated process, aiding replication and evading the immune system, and may contribute to the different cell death process observed in various studies. Nevertheless, recent research in the field of LDs suggests these organelles according to the pathogen and infection conditions may also play roles in immune and inflammatory responses, protecting the host against viral infection. Understanding how SARS-CoV-2 influences LD biogenesis is crucial for developing novel drugs or repurposing existing ones. By targeting host lipid metabolic pathways exploited by the virus, it is possible to impact viral replication and inflammatory responses. This review seeks to discuss and analyze the role of LDs during SARS-CoV-2 infection, specifically emphasizing their involvement in viral replication and the inflammatory response.

Group 2 innate lymphoid cells (ILC2s) play a crucial role in allergic diseases by coordinating a complex network of various effector cell lineages involved in type 2 inflammation. However, their function in regulating airway neutrophil infiltration, a deleterious symptom of severe asthma, remains unknown. Here, we observed ILC2-dependent neutrophil accumulation in the bronchoalveolar lavage fluid (BALF) of allergic mouse models. Chromatography followed by proteomics analysis identified the alarmin high mobility group box-1 (HMGB1) in the supernatant of lung ILC2s initiated neutrophil chemotaxis. Genetic perturbation of Hmgb1 in ILC2s reduced BALF neutrophil numbers and alleviated airway inflammation. HMGB1 was loaded onto the membrane of lipid droplets (LDs) released from activated lung ILC2s. Genetic inhibition of LD accumulation in ILC2s significantly decreased extracellular HMGB1 abundance and BALF neutrophil infiltration. These findings unveil a previously uncharacterized extracellular LD-mediated immune signaling delivery pathway by which ILC2s regulate airway neutrophil infiltration during allergic inflammation.

Type 2 innate lymphoid cells (ILC2s) have emerged as pivotal regulators in the pathogenesis of diseases, with their roles in inflammation, metabolism, and tissue homeostasis becoming increasingly recognized. This review provides an overview of the current understanding of ILC2s in inflammation and metabolic disorders, including their functional contributions. Moreover, we will discuss how these cells adapt their metabolic processes to support their function and survival and how their metabolic requirements change under different physiological and pathological conditions. Lastly, we will review recent omics studies that have provided insights into the molecular and cellular characteristics of ILC2s. This includes transcriptomic, proteomic, and metabolomic analyses that have elucidated the gene expression profiles, protein interactions, and metabolic networks, respectively, associated with ILC2s. These studies have advanced our understanding of the functional diversity of ILC2s and their involvement in metabolic disease.

Group 2 Innate Lymphoid Cells (ILC2) are critical drivers of both innate and adaptive type 2 immune responses, known to orchestrate processes involved in tissue restoration and wound healing. In addition, ILC2 have been implicated in chronic inflammatory barrier disorders in type 2 immunopathologies such as allergic rhinitis and asthma. ILC2 in the context of allergen-driven airway inflammation have recently been shown to influence local and systemic metabolism, as well as being rich in lipid-storing organelles called lipid droplets. However, mechanisms of ILC2 lipid anabolism and catabolism remain largely unknown and the impact of these metabolic processes in regulating ILC2 phenotypes and effector functions has not been extensively characterized. ILC2 phenotypes and effector functions are shaped by their metabolic status, and determining the metabolic requirements of ILC2 is critical in understanding their role in type 2 immune responses and their associated pathophysiology. We detail here a novel experimental method of implementing flow cytometry for large scale analysis of fatty acid uptake, storage of neutral lipids, and fatty acid oxidation in primary murine ILC2 with complementary morphological analysis of lipid storage using confocal microscopy. By combining flow cytometry and confocal microscopy, we can identify the metabolic lipid requirements for ILC2 functions as well as characterize the phenotype of lipid storage in ILC2. Linking lipid metabolism pathways to ILC2 phenotypes and effector functions is critical for the assessment of novel pharmaceutical strategies to regulate ILC2 functions in type 2 immunopathologies.

The correlation between liver disease and the progression of ulcerative colitis (UC) has remained elusive. In this study, it demonstrates that liver injury is intricately linked to the heightened severity of UC in patients, and causes more profound intestinal damage during DSS-induced colitis in mice. Metabolomics analysis of plasma from liver cirrhosis patients shows liver injury compromising nicotinamide supply for NAD+ biosynthesis in the intestine. Subsequent investigation identifies intestinal group 2 innate lymphoid cells (ILC2s) are responsible for liver injury-exacerbated colitis. Reconstitution of ILC2s or the restoration of NAD+ metabolism proves effective in relieving liver injury-aggravated experimental colitis. Mechanistically, the NAD+ salvage pathway regulates gut ILC2s in a cell-intrinsic manner by supporting the generation of succinate, which fuels the electron transport chain to sustaining ILC2s function. This research deepens the understanding of cellular and molecular mechanisms in liver disease-UC interplay, identifying a metabolic target for innovative treatments in liver injury-complicated colitis.

Neutrophils are key players in the innate immune system, actively migrating to sites of inflammation in the highly energetic process of chemotaxis. In this study, we focus on the role of acyl-CoA: diacylglycerol acyltransferase 1 (DGAT1), an enzyme that catalyzes the synthesis of triglycerides, the major form of stored energy, in neutrophil chemotaxis.

Using a mouse model of psoriasis, we show that DGAT1-deficiency reduces energy-demanding neutrophil infiltration to the site of inflammation, but this inhibition is not caused by decreased glycolysis and reduced ATP production by neutrophils lacking DGAT1. Flow cytometry and immunohistochemistry analysis demonstrate that DGAT1 also does not influence lipid accumulation in lipid droplets during inflammation. Interestingly, as has been shown previously, a lack of DGAT1 leads to an increase in the concentration of retinoic acid, and here, using real-time PCR and publicly-available next-generation RNA sequencing datasets, we show the upregulation of retinoic acid-responsive genes in Dgat1KO neutrophils. Furthermore, supplementation of WT neutrophils with exogenous retinoic acid mimics DGAT1-deficiency in the inhibition of neutrophil chemotaxis in in vitro transwell assay.

These results suggest that impaired skin infiltration by neutrophils in Dgat1KO mice is a result of the inhibitory action of an increased concentration of retinoic acid, rather than impaired lipid metabolism in DGAT1-deficient mice.

Ferroptosis is a pervasive non-apoptotic form of cell death highly relevant in various degenerative diseases and malignancies. The hallmark of ferroptosis is uncontrolled and overwhelming peroxidation of polyunsaturated fatty acids contained in membrane phospholipids, which eventually leads to rupture of the plasma membrane. Ferroptosis is unique in that it is essentially a spontaneous, uncatalyzed chemical process based on perturbed iron and redox homeostasis contributing to the cell death process, but that it is nonetheless modulated by many metabolic nodes that impinge on the cells' susceptibility to ferroptosis. Among the various nodes affecting ferroptosis sensitivity, several have emerged as promising candidates for pharmacological intervention, rendering ferroptosis-related proteins attractive targets for the treatment of numerous currently incurable diseases. Herein, the current members of a Germany-wide research consortium focusing on ferroptosis research, as well as key external experts in ferroptosis who have made seminal contributions to this rapidly growing and exciting field of research, have gathered to provide a comprehensive, state-of-the-art review on ferroptosis. Specific topics include: basic mechanisms, in vivo relevance, specialized methodologies, chemical and pharmacological tools, and the potential contribution of ferroptosis to disease etiopathology and progression. We hope that this article will not only provide established scientists and newcomers to the field with an overview of the multiple facets of ferroptosis, but also encourage additional efforts to characterize further molecular pathways modulating ferroptosis, with the ultimate goal to develop novel pharmacotherapies to tackle the various diseases associated with - or caused by - ferroptosis.

Metabolic reprogramming is a k`ey hallmark of tumors, developed in response to hypoxia and nutrient deficiency during tumor progression. In both cancer and immune cells, there is a metabolic shift from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, also known as the Warburg effect, which then leads to lactate acidification, increased lipid synthesis, and glutaminolysis. This reprogramming facilitates tumor immune evasion and, within the tumor microenvironment (TME), cancer and immune cells collaborate to create a suppressive tumor immune microenvironment (TIME). The growing interest in the metabolic reprogramming of the TME, particularly its significance in colorectal cancer (CRC)-one of the most prevalent cancers-has prompted us to explore this topic. CRC exhibits abnormal glycolysis, glutaminolysis, and increased lipid synthesis. Acidosis in CRC cells hampers the activity of anti-tumor immune cells and inhibits the phagocytosis of tumor-associated macrophages (TAMs), while nutrient deficiency promotes the development of regulatory T cells (Tregs) and M2-like macrophages. In CRC cells, activation of G-protein coupled receptor 81 (GPR81) signaling leads to overexpression of programmed death-ligand 1 (PD-L1) and reduces the antigen presentation capability of dendritic cells. Moreover, the genetic and epigenetic cell phenotype, along with the microbiota, significantly influence CRC metabolic reprogramming. Activating RAS mutations and overexpression of epidermal growth factor receptor (EGFR) occur in approximately 50% and 80% of patients, respectively, stimulating glycolysis and increasing levels of hypoxia-inducible factor 1 alpha (HIF-1α) and MYC proteins. Certain bacteria produce short-chain fatty acids (SCFAs), which activate CD8+ cells and genes involved in antigen processing and presentation, while other mechanisms support pro-tumor activities. The use of immune checkpoint inhibitors (ICIs) in selected CRC patients has shown promise, and the combination of these with drugs that inhibit aerobic glycolysis is currently being intensively researched to enhance the efficacy of immunotherapy.

Immunoregulatory mechanisms established in the lymphoid organs are vital for preventing autoimmunity. However, the presence of similar mechanisms in non-lymphoid tissues remains unclear. Through transcriptomic and lipidomic analyses, we find a negative association between psoriasis and fatty acid metabolism, as well as Th2 signature. Homeostatic expression of liver X receptor (LXR) and peroxisome proliferator-activated receptor gamma (PPARγ) is essential for maintaining fatty acid metabolism and for conferring resistance to psoriasis in mice. Perturbation of signal transducer and activator of transcription 6 (STAT6) diminishes the homeostatic levels of LXR and PPARγ. Furthermore, mice lacking STAT6, interleukin 4 receptor alpha (IL-4Rα), or IL-13, but not IL-4, exhibit increased susceptibility to psoriasis. Under steady state, innate lymphoid cells (ILCs) are the primary producers of IL-13. In human skin, inhibiting tonic type 2 immunity exacerbates psoriasis-like inflammation and IL-17A, while activating LXR or PPARγ inhibits them. Hence, we propose that tonic type 2 immunity, driven by IL-13-producing ILCs, represents a crucial tissue checkpoint that represses autoimmunity and maintains lipid homeostasis in the skin.

Cellular metabolism is a crucial determinant of immune cell fate and function. Extensive studies have demonstrated that metabolic decisions influence immune cell activation, differentiation, and cellular capacity, in the process impacting an organism's ability to stave off infection or recover from injury. Conversely, metabolic dysregulation can contribute to the severity of multiple disease conditions including autoimmunity, alloimmunity, and cancer. Emerging data also demonstrate that metabolic cues and profiles can influence the success or failure of adoptive cellular therapies. Importantly, immunometabolism is not one size fits all; and different immune cell types, and even subdivisions within distinct cell populations utilize different metabolic pathways to optimize function. Metabolic preference can also change depending on the microenvironment in which cells are activated. For this reason, understanding the metabolic requirements of different subsets of immune cells is critical to therapeutically modulating different disease states or maximizing cellular function for downstream applications. Fatty acid oxidation (FAO), in particular, plays multiple roles in immune cells, providing both pro- and anti-inflammatory effects. Herein, we review the major metabolic pathways available to immune cells, then focus more closely on the role of FAO in different immune cell subsets. Understanding how and why FAO is utilized by different immune cells will allow for the design of optimal therapeutic interventions targeting this pathway.

Adipose tissue group 2 innate lymphoid cells (ILC2s) help maintain metabolic homeostasis by sustaining type 2 immunity and promoting adipose beiging. Although impairment of the ILC2 compartment contributes to obesity-associated insulin resistance, the underlying mechanisms have not been elucidated. Here, we found that ILC2s in obese mice and humans exhibited impaired liver kinase B1 (LKB1) activation. Genetic ablation of LKB1 disrupted ILC2 mitochondrial metabolism and suppressed ILC2 responses, resulting in exacerbated insulin resistance. Mechanistically, LKB1 deficiency induced aberrant PD-1 expression through activation of NFAT, which in turn enhanced mitophagy by suppressing Bcl-xL expression. Blockade of PD-1 restored the normal functions of ILC2s and reversed obesity-induced insulin resistance in mice. Collectively, these data present the LKB1-PD-1 axis as a promising therapeutic target for the treatment of metabolic disease.

Previous research has emphasized the potential benefits of anti-diabetic medications in inhibiting the exacerbation of Chronic Obstructive Pulmonary Disease (COPD), yet the role of anti-diabetic drugs on COPD risk remains uncertain.

This study employed a Mendelian randomization (MR) approach to evaluate the causal association of genetic variations related to six classes of anti-diabetic drug targets with COPD. The primary outcome for COPD was obtained from the Global Biobank Meta-analysis Initiative (GBMI) consortium, encompassing a meta-analysis of 12 cohorts with 81,568 cases and 1,310,798 controls. Summary-level data for HbA1c was derived from the UK Biobank, involving 344,182 individuals. Positive control analysis was conducted for Type 2 Diabetes Mellitus (T2DM) to validate the choice of instrumental variables. The study applied Summary-data-based MR (SMR) and two-sample MR for effect estimation and further adopted colocalization analysis to verify evidence of genetic variations.

SMR analysis revealed that elevated KCNJ11 gene expression levels in blood correlated with reduced COPD risk (OR = 0.87, 95% CI = 0.79-0.95; p = 0.002), whereas an increase in DPP4 expression corresponded with an increased COPD incidence (OR = 1.18, 95% CI = 1.03-1.35; p = 0.022). Additionally, the primary method within MR analysis demonstrated a positive correlation between PPARG-mediated HbA1c and both FEV1 (OR = 1.07, 95% CI = 1.02-1.13; P = 0.013) and FEV1/FVC (OR = 1.08, 95% CI = 1.01-1.14; P = 0.007), and a negative association between SLC5A2-mediated HbA1c and FEV1/FVC (OR = 0.86, 95% CI = 0.74-1.00; P = 0.045). No colocalization evidence with outcome phenotypes was detected (all PP.H4 < 0.7).

This study provides suggestive evidence for anti-diabetic medications' role in improving COPD and lung function. Further updated MR analyses are warranted in the future, following the acquisition of more extensive and comprehensive data, to validate our results.

Helper Th2-type immune responses are essential in allergic airway diseases, including asthma and allergic rhinitis. Recent studies have indicated that group 2 innate lymphoid cells (ILC2s) play a crucial role in the occurrence and development of asthma. However, the metabolic profile of ILC2s and their regulatory mechanisms in asthma remain unclear. Therefore, we established two asthma mouse models: an ovalbumin (OVA)-induced asthma model and an IL-33-induced asthma model. We then used ultra-high-performance liquid chromatography/mass spectrometry (UHPLC/MS) to conduct high-throughput untargeted metabolic analysis of ILC2s in the lung tissues of the asthma models. The identified metabolites primarily consisted of lipids, lipid-like molecules, benzene, organic acids, derivatives, and organic oxidation compounds. Specifically, 34 differentially accumulated metabolites influenced the metabolic profiles of the control and OVA-induced asthma model groups. Moreover, the accumulation of 39 metabolites significantly differed between the Interleukin 33 (IL-33) and control groups. These differentially accumulated metabolites were mainly involved in pathways such as sphingolipid, oxidative phosphorylation, and fatty acid metabolism. This metabolomic study revealed, for the first time, the key metabolites and metabolic pathways of ILC2s, revealing new aspects of cellular metabolism in the context of airway inflammation. These findings not only contribute to unraveling the pathogenesis of asthma but also provide a crucial theoretical foundation for the future development of therapeutic strategies targeting ILC2s.