Unveiling the hidden dangers: a review of non-apoptotic programmed cell death in anesthetic-induced developmental neurotoxicity.

Anesthetic-induced developmental neurotoxicity (AIDN) can arise due to various factors, among which aberrant nerve cell death is a prominent risk factor. Animal studies have reported that repeated or prolonged anesthetic exposure can cause significant neuroapoptosis in the developing brain. Lately, non-apoptotic programmed cell deaths (PCDs), characterized by inflammation and oxidative stress, have gained increasing attention. Substantial evidence suggests that non-apoptotic PCDs are essential for neuronal cell death in AIDN compared to apoptosis. This article examines relevant publications in the PubMed database until April 2024. Only original articles in English that investigated the potential manifestations of non-apoptotic PCD in AIDN were analysed. Specifically, it investigates necroptosis, pyroptosis, ferroptosis, and parthanatos, elucidating the signaling mechanisms associated with each form. Furthermore, this study explores the potential relevance of these non-apoptotic PCDs pathways to the pathological mechanisms underlying AIDN, drawing upon their distinctive characteristics. Despite the considerable challenges involved in translating fundamental scientific knowledge into clinical therapeutic interventions, this comprehensive review offers a theoretical foundation for developing innovative preventive and treatment strategies targeting non-apoptotic PCDs in the context of AIDN.

Wogonin Inhibits Apoptosis and Necroptosis Induced by Nephropathogenic Infectious Bronchitis Virus in Chicken Renal Tubular Epithelial Cells.

NIBV is an acute and highly contagious virus that has a major impact on the poultry industry. Wogonin, as a flavonoid drug, has antiviral effects, but there have been no reports indicating its role in renal injury caused by NIBV infection. The aim of this study is to investigate the antiviral effect of wogonin against NIBV. Renal tubular epithelial cells were isolated and cultured, and divided into four groups: Con, Con+Wog, NIBV and NIBV+Wog. We found that wogonin significantly inhibited the copy number of NIBV and significantly alleviated NIBV-induced cell apoptosis and necrosis. Moreover, wogonin inhibited the reduction in mitochondrial membrane potential and the aberrant opening of mPTP caused by NIBV. In conclusion, wogonin can protect renal tubular epithelial cells from damage by inhibiting the replication of NIBV and preventing mitochondrial apoptosis and necroptosis induced by NIBV.

Regulation of Zfp36 by ISGF3 and MK2 restricts the expression of inflammatory cytokines during necroptosis stimulation.

Necrosome activation following TLR- or cytokine receptor-signaling results in cell death by necroptosis which is characterized by the rupture of cell membranes and the consequent release of intracellular contents to the extracellular milieu. While necroptosis exacerbates various inflammatory diseases, the mechanisms through which the inflammatory responses are regulated are not clear. We show that the necrosome activation of macrophages results in an upregulation of various pathways, including the mitogen-activated protein kinase (MAPK) cascade, which results in an elevation of the inflammatory response and consequent expression of several cytokines and chemokines. Programming for this upregulation of inflammatory response occurs during the early phase of necrosome activation and proceeds independently of cell death but depends on the activation of the receptor-interacting protein kinase-1 (RipK1). Interestingly, necrosome activation also results in an upregulation of IFNß, which in turn exerts an inhibitory effect on the maintenance of inflammatory response through the repression of MAPK-signaling and an upregulation of Zfp36. Activation of the interferon-induced gene factor-3 (ISGF3) results in the expression of ZFP36 (TTP), which induces the post-transcriptional degradation of mRNAs of various inflammatory cytokines and chemokines through the recognition of AU-rich elements in their 3'UTR. Furthermore, ZFP-36 inhibits IFNß-, but not TNFα- induced necroptosis. Overall, these results reveal the molecular mechanism through which IFNß, a pro-inflammatory cytokine, induces the expression of ZFP-36, which in turn inhibits necroptosis and halts the maintenance of the inflammatory response.

The Function of Necroptosis and Its Treatment Target in IBD.

Inflammatory bowel disease (IBD), which encompasses Crohn's disease (CD) and ulcerative colitis (UC), is a complicated illness whose exact cause is yet unknown. Necroptosis is associated with IBD pathogenesis, leading to intestinal barrier abnormalities and uncontrolled inflammation. Molecules involved in necroptosis, however, exhibit different expression levels in IBD and its associated colorectal cancer. Multiple studies have shown that inhibiting these molecules alleviates necroptosis-induced IBD. Moreover, due to the severe scarcity of clinical medications for treating IBD caused by necroptosis, we review the various functions of crucial necroptosis molecules in IBD, the stimuli regulating necroptosis, and the current emerging therapeutic strategies for treating IBD-associated necroptosis. Eventually, understanding the pathogenesis of necroptosis in IBD will enable the development of additional therapeutic approaches for the illness.

Implications of inflammatory cell death-PANoptosis in health and disease.

Regulated cell death (RCD) pathways, such as pyroptosis, apoptosis, and necroptosis, are essential for maintaining the body's balance, defending against pathogens, and eliminating abnormal cells that could lead to diseases like cancer. Although these pathways operate through distinct mechanisms, recent genetic and pharmacological studies have shown that they can interact and influence each other. The concept of "PANoptosis" has emerged, highlighting the interplay between pyroptosis, apoptosis, and necroptosis, especially during cellular responses to infections. This article provides a concise overview of PANoptosis and its molecular mechanisms, exploring its implications in various diseases. The review focuses on the extensive interactions among different RCD pathways, emphasizing the role of PANoptosis in infections, cytokine storms, inflammatory diseases, and cancer. Understanding PANoptosis is crucial for developing novel treatments for conditions involving infections, sterile inflammations, and cancer.

The protective role of Cordyceps cicadae and its active ingredient myriocin against sodium iodate-induced age-related macular degeneration via an anti-necroptotic TNF-RIPK1/3 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Cordyceps cicadae (C.cicadae), named "Chan Hua", an anamorph of Isaria cicadae Miquel, is an entomogenous complex formed by fungi parasitizing on the larvae of cicadas and belongs to the Claviciptaceae family and the genus Codyceps, which traditionally holds a significant place in Chinese ethnopharmacology, specifically for eye clarity and as a remedy for age-related ocular conditions. The underlying mechanisms contributing to its eyesight enhancement and potential effectiveness against Age-related macular degeneration (AMD) remain unexplored. AIM OF THE STUDY: This study aims to elucidate the protective role of C.cicadae and its active ingredient, Myriocin (Myr), against AMD. MATERIALS AND METHODS: A chemical inducer was employed to make retinal pigment epithelium (RPE) damage in vitro and in vivo. The key ingredients of C.cicadae and their related mechanisms for anti-AMD were studied through bioinformatic analysis and molecular biological approaches. RESULTS: Myr was identified through high-performance liquid chromatography (HPLC) as an active ingredient in C.cicadae, and demonstrated a protective effect on RPE cells, reducing the structural damage and cell death induced by sodium iodate (SI). Further, Myr reduced eyelid secretions in AMD mice and restored their retinal structure and function. The differentially expressed genes (DEGs) in Myr treatment are primarily associated with TNF and Necroptosis signaling pathways. Molecular docking indicated a strong affinity between TNF and Myr. Myr inhibited the TNF signaling pathway thereby reducing the expression of inflammatory factors in ARPE-19 cells. Additionally, Myr had consistent action with the necroptosis inhibitor Necrostatin-1 (Nec-1), inhibited the RIPK1/RIPK3/MLKL pathway thereby protecting ARPE-19 cells. CONCLUSION: The findings present Myr, as a potent protector against SI-induced AMD, predominantly through modulation of the TNF-RIPK1/RIPK3/MLKL signaling pathway, offering the insights of therapeutic C.cicadae as viable candidates for AMD treatment.

PANoptosis: a novel target for cardiovascular diseases.

PANoptosis is a unique innate immune inflammatory lytic cell death pathway initiated by an innate immune sensor and driven by caspases and RIPKs. As a distinct pathway, the execution of PANoptosis cannot be hindered by targeting other cell death pathways, such as pyroptosis, apoptosis, or necroptosis. Instead, targeting key PANoptosome components can serve as a strategy to prevent this form of cell death. Given the physiological relevance in several diseases, PANoptosis is a pivotal therapeutic target. Notably, previous research has primarily focused on the role of PANoptosis in cancer and infectious and inflammatory diseases. By contrast, its role in cardiovascular diseases has not been comprehensively discussed. Here, we review the available evidence on PANoptosis in cardiovascular diseases, including cardiomyopathy, atherosclerosis, myocardial infarction, myocarditis, and aortic aneurysm and dissection, and explore a variety of agents that target PANoptosis, with the overarching goal of providing a novel complementary approach to combatting cardiovascular diseases.

HSPA8 inhibitors augment cancer chemotherapeutic effectiveness via potentiating necroptosis.

Our recent work has uncovered a novel function of HSPA8 as an amyloidase, capable of dismantling the RHIM-containing protein fibrils to suppress necroptosis. However, the impact of HSPA8 inhibitors on cancer regression via necroptosis remains unexplored. In this study, we conducted a comprehensive investigation to assess the potential of HSPA8 inhibitors in enhancing necroptosis both in vitro and in vivo. Our findings indicate that pharmacologic inhibition of HSPA8, achieved either through VER (VER-155008) targeting the nucleotide binding domain or pifithrin-µ targeting the substrate binding domain of HSPA8, significantly potentiates necroptosis induced by diverse treatments in cellular assays. These inhibitors effectively disrupt the binding of HSPA8 to the RHIM protein, impeding its regulatory function on RHIM amyloid formation. Importantly, HSPA8 inhibitors significantly enhanced cancer cell sensitivity to microtubule-targeting agents (MTAs) in vitro, while reversing chemoresistance and facilitating tumor regression by augmenting necroptosis in vivo. Our findings suggest a promising therapeutic approach to cancer through necroptosis modulation via HSPA8 targeting, particularly in combination with MTA drugs for enhanced treatment efficacy.

Exploring cell death mechanisms in spheroid cultures using a novel application of the RIP3-caspase3-assay.

This study explores the application of the RIP3-caspase3-assay in heterogeneous spheroid cultures to analyze cell death pathways, emphasizing the nuanced roles of apoptosis and necroptosis. By employing directly conjugated monoclonal antibodies, we provide detailed insights into the complex mechanisms of cell death. Our findings demonstrate the assay's capability to differentiate between RIP1-independent apoptosis, necroptosis, and RIP1-dependent apoptosis, marking a significant advancement in organoid research. Additionally, we investigate the effects of TNFα on isolated intestinal epithelial cells, revealing a concentration-dependent response and an adaptive or threshold reaction to TNFα-induced stress. The results indicate a preference for RIP1-independent cell death pathways upon TNFα stimulation, with a notable increase in apoptosis and a secondary role of necroptosis. Our research underscores the importance of the RIP3-caspase3-assay in understanding cell death mechanisms in organoid cultures, offering valuable insights for disease modeling and the development of targeted therapies. The assay's adaptability and robustness in spheroid cultures enhances its potential as a tool in personalized medicine and translational research.

Initiator cell death event induced by SARS-CoV-2 in the human airway epithelium.

Virus-induced cell death is a key contributor to COVID-19 pathology. Cell death induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is well studied in myeloid cells but less in its primary host cell type, angiotensin-converting enzyme 2 (ACE2)-expressing human airway epithelia (HAE). SARS-CoV-2 induces apoptosis, necroptosis, and pyroptosis in HAE organotypic cultures. Single-cell and limiting-dilution analysis revealed that necroptosis is the primary cell death event in infected cells, whereas uninfected bystanders undergo apoptosis, and pyroptosis occurs later during infection. Mechanistically, necroptosis is induced by viral Z-RNA binding to Z-DNA-binding protein 1 (ZBP1) in HAE and lung tissues from patients with COVID-19. The Delta (B.1.617.2) variant, which causes more severe disease than Omicron (B1.1.529) in humans, is associated with orders of magnitude-greater Z-RNA/ZBP1 interactions, necroptosis, and disease severity in animal models. Thus, Delta induces robust ZBP1-mediated necroptosis and more disease severity.

A confusion of pathways: Discerning cell death mechanisms in SARS-CoV-2 infection.

Upon SARS-CoV-2 infection, infected cells undergo necroptosis, whereas delayed apoptosis and pyroptosis occur in uninfected, bystander cells, thus providing a plausible explanation for the extensive injury among myriad uninfected cells.

Leveraging single-cell sequencing analysis and bulk-RNA sequencing analysis to forecast necroptosis in cutaneous melanoma prognosis.

Cutaneous melanoma, a malignancy of melanocytes, presents a significant challenge due to its aggressive nature and rising global incidence. Despite advancements in treatment, the variability in patient responses underscores the need for further research into novel therapeutic targets, including the role of programmed cell death pathways such as necroptosis. The melanoma datasets used for analysis, GSE215120, GSE19234, GSE22153 and GSE65904, were downloaded from the GEO database. The melanoma data from TCGA were downloaded from the UCSC website. Using single-cell sequencing, we assess the heterogeneity of necroptosis in cutaneous melanoma, identifying distinct cell clusters and necroptosis-related gene expression patterns. A combination of 101 machine learning algorithms was employed to construct a necroptosis-related signature (NRS) based on key genes associated with necroptosis. The prognostic value of NRS was evaluated in four cohorts (one TCGA and three GEO cohorts), and the tumour microenvironment (TME) was analysed to understand the relationship between necroptosis, tumour mutation burden (TMB) and immune infiltration. Finally, we focused on the role of key target TSPAN10 in the prognosis, pathogenesis, immunotherapy relevance and drug sensitivity of cutaneous melanoma. Our study revealed significant heterogeneity in necroptosis among melanoma cells, with a higher prevalence in epithelial cells, myeloid cells and fibroblasts. The NRS, developed through rigorous machine learning techniques, demonstrated robust prognostic capabilities, distinguishing high-risk patients with poorer outcomes in all cohorts. Analysis of the TME showed that high NRS scores correlated with lower TMB and reduced immune cell infiltration, indicating a potential mechanism through which necroptosis influences melanoma progression. Finally, TSPAN10 has been identified as a key target for cutaneous melanoma and is highly associated with poor prognosis. The findings highlight the complex role of necroptosis in cutaneous melanoma and introduce the NRS as a novel prognostic tool with potential to guide therapeutic decisions.

Influenza virus infection activates TAK1 to suppress RIPK3-independent apoptosis and RIPK1-dependent necroptosis.

Many DNA viruses develop various strategies to inhibit cell death to facilitate their replication. However, whether influenza A virus (IAV), a fast-replicating RNA virus, attenuates cell death remains unknown. Here, we report that IAV infection induces TAK1 phosphorylation in a murine alveolar epithelial cell line (LET1) and a murine fibroblastoma cell line (L929). The TAK1-specific inhibitor 5Z-7-Oxzeneonal (5Z) and TAK1 knockout significantly enhance IAV-induced apoptosis, as evidenced by increased PARP, caspase-8, and caspase-3 cleavage. TAK1 inhibition also increases necroptosis as evidenced by increased RIPK1S166, RIPK3T231/S232, and MLKLS345 phosphorylation. Mechanistically, TAK1 activates IKK, which phosphorylates RIPK1S25 and inhibits its activation. TAK1 also activates p38 and its downstream kinase MK2, which phosphorylates RIPK1S321 but does not affect RIPK1 activation. Further investigation revealed that the RIPK1 inhibitor Nec-1 and RIPK1 knockout abrogate IAV-induced apoptosis and necroptosis; re-expression of wild-type but not kinase-dead (KD)-RIPK1 restores IAV-induced cell death. ZBP1 knockout abrogates IAV-induced cell death, whereas RIPK3 knockout inhibits IAV-induced necroptosis but not apoptosis. 5Z treatment enhances IAV-induced cell death and slightly reduces the inflammatory response in the lungs of H1N1 virus-infected mice and prolongs the survival of IAV-infected mice. Our study provides evidence that IAV activates TAK1 to suppress RIPK1-dependent apoptosis and necroptosis, and that RIPK3 is required for IAV-induced necroptosis but not apoptosis in epithelial cells.

Necroptosis in recurrent implantation failure: A bioinformatics analysis of key genes and therapeutic targets.

Recurrent implantation failure (RIF), a major issue in assisted reproductive technology (ART), may be influenced by necroptosis, a form of cell death linked to several diseases. This study was aimed at investigating the involvement of necroptosis in RIF. Using RNA-sequencing data from the Gene Expression Omnibus database, we identified differentially expressed necroptosis-related genes (DENRGs) in RIF patients compared with those in controls. Functional enrichment, protein-protein interaction (PPI) networks, and transcription factor (TF) regulatory networks were analyzed to identify key genes. Immune cell infiltration was analyzed using the single-sample gene set enrichment analysis (ssGSEA) algorithm. Finally, potential therapeutic drugs targeting key genes were explored using a Drug Gene Interaction Database. In total, 20 DENRGs associated with RIF were identified, with a focus on 6 key genes (MLKL, FASLG, XIAP, CASP1, BIRC3, and TLR3) implicated in necroptosis and immune processes. These genes were used to develop a predictive model for RIF, which was validated in 2 datasets. The model and TF network analysis underscored the importance of TLR3. Immune infiltration analysis showed reduced levels of 16 immune cells in RIF patients, highlighting immune system alterations. Several drugs targeting CASP1, such as nivocasan and emricasan, were identified as potential treatments. The study sheds light on the role of necroptosis in RIF, identifying key genes and immune alterations that could serve as biomarkers and therapeutic targets. These findings pave the way for future experimental research and clinical applications targeting necroptosis in RIF treatment.

Extracellular vesicles from alveolar macrophages harboring phagocytosed methicillin-resistant Staphylococcus aureus induce necroptosis.

Methicillin-resistant Staphylococcus aureus (MRSA) infection, a major cause of hospital- and community-acquired pneumonia, still has a high mortality rate. Extracellular vesicles (EVs), as crucial mediators of intercellular communication, have a significant impact on infectious diseases. However, the role of EVs from alveolar macrophages (AMs) in MRSA pneumonia remains unclear. We report that AMs phagocytose MRSA and release more EVs in mice with MRSA pneumonia. EVs from AMs harboring phagocytosed MRSA exhibit significant proinflammatory effects and induce necroptosis by delivering tumor necrosis factor α (TNF-α) and miR-146a-5p. Mechanically, the upregulated miR-146a-5p in these EVs enhances the phosphorylation of RIPK1, RIPK3, and MLKL by targeting TNF receptor-associated factor 6 (TRAF6), thereby promoting TNF-α-induced necroptosis. The combination of a TNF-α antagonist and an miR-146a-5p antagomir effectively improves the outcomes of mice with MRSA pneumonia. Overall, we reveal the pronecrotic effect of EVs from MRSA-infected AMs and provide a promising target for the prevention and treatment of MRSA pneumonia.

Identification of necroptosis-related genes in ankylosing spondylitis by bioinformatics and experimental validation.

The pathogenesis of ankylosing spondylitis (AS) remains unclear, and while recent studies have implicated necroptosis in various autoimmune diseases, an investigation of its relationship with AS has not been reported. In this study, we utilized the Gene Expression Omnibus database to compare gene expressions between AS patients and healthy controls, identifying 18 differentially expressed necroptosis-related genes (DENRGs), with 8 upregulated and 10 downregulated. Through the application of three machine learning algorithms-least absolute shrinkage and selection operation, support vector machine-recursive feature elimination and random forest-two hub genes, FASLG and TARDBP, were pinpointed. These genes demonstrated high specificity and sensitivity for AS diagnosis, as evidenced by receiver operating characteristic curve analysis. These findings were further supported by external datasets and cellular experiments, which confirmed the downregulation of FASLG and upregulation of TARDBP in AS patients. Immune cell infiltration analysis suggested that CD4+ T cells, CD8+ T cells, NK cells and neutrophils may be associated with the development of AS. Notably, in the group with high FASLG expression, there was a significant infiltration of CD8+ T cells, memory-activated CD4+ T cells and resting NK cells, with relatively less infiltration of memory-resting CD4+ T cells and neutrophils. Conversely, in the group with high TARDBP expression, there was enhanced infiltration of naïve CD4+ T cells and M0 macrophages, with a reduced presence of memory-resting CD4+ T cells. In summary, FASLG and TARDBP may contribute to AS pathogenesis by regulating the immune microenvironment and immune-related signalling pathways. These findings offer new insights into the molecular mechanisms of AS and suggest potential new targets for therapeutic strategies.

Spotlight on necroptosis: Role in pathogenesis and therapeutic potential of intervertebral disc degeneration.

Intervertebral disc degeneration (IDD) is the leading cause of low back pain, which is one of the major factors leading to disability and severe economic burden. Necroptosis is an important form of programmed cell death (PCD), a highly regulated caspase-independent type of cell death that is regulated by receptor-interacting protein kinase 1 (RIPK1), RIPK3 and mixed lineage kinase domain-like protein (MLKL)-mediated, play a key role in the pathophysiology of various inflammatory, infectious and degenerative diseases. Recent studies have shown that necroptosis plays an important role in the occurrence and development of IDD. In this review, we provide an overview of the initiation and execution of necroptosis and explore in depth its potential mechanisms of action in IDD. The analysis focuses on the connection between NP cell necroptosis and mitochondrial dysfunction-oxidative stress pathway, inflammation, endoplasmic reticulum stress, apoptosis, and autophagy. Finally, we evaluated the possibility of treating IDD by inhibiting necroptosis, and believed that targeting necroptosis may be a new strategy to alleviate the symptoms of IDD.

Ursolic acid improves necroptosis via STAT3 signaling in intestinal ischemia/reperfusion injury.

Intestinal ischemia/reperfusion injury (IRI) poses a serious threat to human survival and quality of life with high mortality and morbidity rates. The current absence of effective treatments for intestinal IRI highlights the urgent need to identify new therapeutic targets. Ursolic acid (UA), a pentacyclic triterpene natural compound, has been shown to possess various pharmacological properties including intestinal protection. However, its potential protective efficacy on intestinal IRI remains elusive. This study aimed to investigate the effect of UA on intestinal IRI and explore the underlying mechanisms. To achieve this, we utilized network pharmacology to analyze the mechanism of UA in intestinal IRI and assessed UA's effects on intestinal IRI using a mouse model of superior mesenteric artery occlusion/reperfusion and an in vitro model of oxygen-glucose deprivation and reperfusion-induced IEC-6 cells. Our results demonstrated that UA improved necroptosis through the RIP1/RIP3/MLKL pathway, reduced necroinflammation via the HMGB1/TLR4/NF-κB pathway, attenuated morphological damage, and enhanced intestinal barrier function. Furthermore, UA pretreatment downregulated the phosphorylation level of signal transducer and activator of transcription 3 (STAT3). The effects of UA were attenuated by the STAT3 agonist Colivelin. In conclusion, our study suggests that UA can improve intestinal IRI by inhibiting necroptosis in enterocytes via the suppression of STAT3 activation. These results provide a theoretical basis for UA treatment of intestinal IRI and related clinical diseases.

Necroptosis plays a role in TL1A-induced airway inflammation and barrier damage in asthma.

BACKGROUND: Airway epithelial cell (AEC) necroptosis contributes to airway allergic inflammation and asthma exacerbation. Targeting the tumor necrosis factor-like ligand 1 A (TL1A)/death receptor 3 (DR3) axis has a therapeutic effect on asthmatic airway inflammation. The role of TL1A in mediating necroptosis of AECs challenged with ovalbumin (OVA) and its contribution to airway inflammation remains unclear. METHODS: We evaluated the expression of the receptor-interacting serine/threonine-protein kinase 3(RIPK3) and the mixed lineage kinase domain-like protein (MLKL) in human serum and lung, and histologically verified the level of MLKL phosphorylation in lung tissue from asthmatics and OVA-induced mice. Next, using MLKL knockout mice and the RIPK3 inhibitor GSK872, we investigated the effects of TL1A on airway inflammation and airway barrier function through the activation of necroptosis in experimental asthma. RESULTS: High expression of necroptosis marker proteins was observed in the serum of asthmatics, and necroptosis was activated in the airway epithelium of both asthmatics and OVA-induced mice. Blocking necroptosis through MLKL knockout or RIPK3 inhibition effectively attenuated parabronchial inflammation, mucus hypersecretion, and airway collagen fiber accumulation, while also suppressing type 2 inflammatory factors secretion. In addition, TL1A/ DR3 was shown to act as a death trigger for necroptosis in the absence of caspases by silencing or overexpressing TL1A in HBE cells. Furthermore, the recombinant TL1A protein was found to induce necroptosis in vivo, and knockout of MLKL partially reversed the pathological changes induced by TL1A. The necroptosis induced by TL1A disrupted the airway barrier function by decreasing the expression of tight junction proteins zonula occludens-1 (ZO-1) and occludin, possibly through the activation of the NF-κB signaling pathway. CONCLUSIONS: TL1A-induced airway epithelial necroptosis plays a significant role in promoting airway inflammation and barrier dysfunction in asthma. Inhibition of the TL1A-induced necroptosis pathway could be a promising therapeutic strategy.