搜索结果：Cellular & molecular biology letters

Primary breast lymphoma is a rare malignancy that accounts for less than 1% of non-Hodgkin lymphomas. Diffuse large B-cell lymphoma is the most common subtype, whereas follicular lymphoma (FL) accounts for only a small proportion of cases. Most FL cases involving the breast represent secondary involvement by systemic disease, and true primary breast FL is uncommon. Molecular characterization of primary breast FL has rarely been reported, and its genetic landscape remains poorly understood. We report a case of primary breast FL, grade 3A, in a 55-year-old woman who presented with a palpable breast mass. Core needle biopsy revealed an atypical follicular lymphoid proliferation composed of centrocytes and numerous centroblasts (> 15 cells/high-power field). Immunohistochemistry revealed positivity for CD20, PAX5, CD10, and BCL6, with weak BCL2 expression, and a Ki-67 proliferation index of approximately 30%. Fluorescence in situ hybridization did not detect IGH::BCL2, BCL6, or MYC rearrangements but demonstrated copy-number gains involving BCL2, BCL6, MYC, and IGH. Next-generation sequencing identified biallelic CREBBP mutations and a FOXO1 mutation. Clonality studies confirmed a clonal IGK rearrangement in the breast lesion. Staging work-up with positron emission tomography/computed tomography showed disease confined to the breast (stage IE). The patient was treated with R-CHOP chemotherapy followed by involved-site radiotherapy. Our findings support the existence of a subset of extranodal follicular lymphomas lacking an IGH::BCL2 rearrangement and highlight alternative pathways of lymphomagenesis with implications for classification and diagnosis. The identification of biallelic CREBBP mutations and a FOXO1 mutation provides molecular insight into extranodal FL biology, suggesting an overlap with nodal FL while supporting alternative oncogenic pathways in extranodal disease.

Mutations in DNA damage repair (DDR) genes lead to genomic instability, driving a range of degenerative syndromes. In addition to promoting mutation accumulation, unrepaired DNA damage can leak into the cytosol and activate innate immune-sensing pathways, particularly the cGAS-STING axis. However, the extent to which cGAS causally contributes to organismal pathology in DDR syndromes in vivo remains unresolved. Here, we genetically model ataxia telangiectasia (A-T) and Bloom syndrome in the short-lived turquoise killifish (Nothobranchius furzeri) and demonstrate that genetic disruption of cgas in the A-T model partially ameliorates germline failure, hepatic senescence, and cerebellar neuroinflammation. Unexpectedly, cgas loss also reversed cellular hallmarks of genome instability, including reduced micronuclei, improved telomere integrity, and restored H3K9me3-marked heterochromatin landscape, consistent with STING-independent nuclear functions of cGAS that influence DNA repair and chromatin. Together, these data identify cGAS as a context-dependent amplifier of DDR pathology acting through canonical inflammatory signaling and noncanonical nuclear mechanisms that shape genome stability. Accordingly, our findings support pharmacological cGAS inhibition as a potential strategy for DDR syndromes in settings of chronic DNA damage while highlighting that cgas loss in an otherwise naive background exacerbates pathology and genomic instability, underscoring its essential role in normal physiology.

The growing demand for alternative cancer treatments has intensified interest in photodynamic therapy (PDT), a minimally invasive approach that combines light irradiation with photosensitizing agents (PSs) to achieve localized cytotoxicity. Phenothiazine derivatives are well established as antimicrobial and anticancer PSs, positioning 1,9-dimethyl methylene blue (DMMB) as a promising candidate. However, the photodynamic performance of DMMB against oropharyngeal carcinoma, particularly as a function of photosensitizer concentration and light dose, remains poorly explored. Here, we investigate the molecular interactions and photodynamic effects of DMMB using membrane-mimetic systems based on lipid extracts from human oropharyngeal carcinoma cells (HEp-2), complemented by in vitro cellular assays. Langmuir monolayers revealed strong membrane affinity of DMMB, leading to pronounced monolayer expansion (up to ∼90% at 1.0 μmol/L) and changes in elastic properties. Upon photoactivation, DMMB induced concentration- and light dose-dependent reductions in monolayer surface area, consistent with light-triggered photodynamic effects at the membrane interface. At 0.1 μmol/L, a modest decrease of ∼3.5% was observed, whereas at 1.0 μmol/L the surface area reduction increased from 6.9% to 13.4% as the light dose rose from 1 to 18 J/cm2. FTIR spectroscopy of Langmuir-Schaefer films revealed limited spectral changes mainly associated with interfacial lipid regions, particularly carbonyl hydration and relative intensity variations, while phosphate and acyl-chain regions were largely preserved. Cellular assays were consistent with the interfacial findings. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and LDH (lactate dehydrogenase) assays demonstrated pronounced phototoxicity in HEp-2 cells with no detectable dark toxicity, yielding IC₅₀ values that decreased from 0.82 μmol/L at 1 J/cm2 to 0.35 μmol/L at 18 J/cm2. Increased LDH release and confocal fluorescence microscopy revealed plasma membrane disruption and intracellular damage consistent with light-induced membrane perturbation inferred from the monolayer studies, which may involve lipid oxidation-related processes. Overall, these results support an association between DMMB-membrane interactions and cellular phototoxicity, highlighting how photosensitizer concentration and light dose modulate DMMB photodynamic effects under the investigated experimental conditions. DMMB thus emerges as a promising candidate for further investigation in oropharyngeal carcinoma PDT models.

Frailty is a clinical syndrome of reduced physiological reserve in older adults for which no pharmacological treatment exists and whose cellular basis remains incompletely defined. As life expectancy rises without a comparable extension of healthspan, the absence of a mechanistic account able to guide targeted intervention is a growing clinical problem. The dominant model of primary mitochondrial bioenergetic insufficiency does not accommodate several features of the phenotype. Among the conditions most strongly associated with frailty in aging, obesity, particularly when coupled with sarcopenia, stands out for its rising prevalence and the depth of its systemic metabolic consequences. Drawing on a recent multi-omics characterisation of skeletal muscle in sarcopenic obesity and on the convergent literature in aging metabolism, organelle communication, and redox biology, we propose a complementary framework in which the proximate cellular abnormality of frailty is energetic congestion, a chronic mismatch between substrate input, energetic demand, and the capacity to dispatch the resulting flux through demand-driven oxidative metabolism. In this view the mitochondrion is not failing because fuel is scarce, but because energetic demand declines below the rate at which substrate continues to be delivered, so that substrate persists in relative rather than absolute excess, while mitochondrial adaptability is progressively impaired. The resulting cycle is self-amplifying, anchored in reverse electron transport, and generalises across skeletal muscle, adipose tissue, liver, heart and brain. Strategies that re-engage demand-driven metabolic flux through AMPK activation, substrate restriction, mild mitochondrial uncoupling, modulation of endoplasmic reticulum stress, and clearance of irreversibly congested cells are predicted to produce more durable benefits than energy supplementation, with structured exercise as the prototype of demand-driven recoupling. This perspective offers a path toward a precision pharmacology of frailty grounded in molecular stratification of patients.

Despite extensive characterization of sperm structures, certain specialized subcellular structures are still not well understood. Among these, the posterior ring has been recognized for over half a century; yet, its molecular composition and biological role remain unknown. This research aims to define the molecular components and functional roles of the sperm posterior ring. 3D-rendered confocal microscopy was used to determine the localization and developmental dynamics of SPEM3 and TEX50 in mature spermatozoa and spermatids at different steps of spermiogenesis. Spem3 and Tex50 knockout mouse models were generated to explore their physiological functions. Sperm morphology and ultrastructure were investigated through immunofluorescence along with transmission and scanning electron microscopy, whereas sperm motility was evaluated using computer-assisted sperm analysis. Proteomics, coimmunoprecipitation, and immunoblotting were performed to identify SPEM3 and TEX50 as structurally interdependent interacting components of the posterior ring and to elucidate how their loss disrupts sperm architecture and fertility. We identified SPEM3 as a core component of the posterior ring located at the sperm head-tail linkage. The posterior ring arises from the marginal ring at the acroplaxome periphery during early spermiogenesis. Loss of Spem3 led to severe bending of the head-tail linkage, accompanied by a marked reduction in sperm motility, ultimately leading to male infertility. Furthermore, SPEM3 interacts and colocalizes with TEX50, and deficiency of either protein resulted in similar phenotypes, including disorganization of the posterior ring and postacrosomal region as well as impairment of the sperm connecting piece. These findings establish SPEM3 and TEX50 as critical posterior ring components essential for maintaining postacrosomal integrity and anchoring the sperm head to the tail. By resolving the long unknown molecular composition of the posterior ring, this study provides new mechanistic insight into sperm head-tail integrity and the pathogenesis of certain forms of male infertility.

A general puzzle in stem-cell and ageing biology is why a few cellular clones come to dominate an ageing tissue while otherwise similar neighbours do not, a fate that the average transcriptional state of a cell predicts poorly. Here we ask whether the variability between sister cells of a clone, rather than their transcriptional state, is the property that predicts ageing-associated clonal selection, using the haematopoietic stem cell (HSC) as a tractable test case. We combine heritable lineage tracing with single-cell RNA sequencing across heterochronic and homochronic transplantation models to link early transcriptional states of individual HSC clones to their long-term functional output in vivo. To quantify transcriptional heterogeneity at clonal resolution, we developed a computational framework (scCloneVar) that estimates mean-adjusted gene expression variance and identifies differentially variable genes (DVG). We found that ageing increases transcriptional heterogeneity at both the cellular and clonal levels, reflected by elevated variability in gene expression programs that regulate stem cell activity. We observe polyclonal expansion of HSC independently of the age of the host or the donor mice; however, individual clones in heterochronic transplantations show reduced self-renewal and fitness compared to sister clones in homochronic transplantations, indicating better adaptation of HSC clones in age-matched microenvironments. Strikingly, transcriptional features measured prior to transplantation predict clonal self-renewal at later time points, with transcriptional variability, captured by DVG, providing predictive power beyond that captured by mean expression differences. DVG-associated programs are conserved across mouse and human HSC, are established by middle age, and are enriched in pathways relevant to clonal haematopoiesis and myeloid malignancy risk. Together, our findings support a model in which ageing expands transcriptional heterogeneity that tracks with subsequent clonal selection, rendering clonal fate partially predictable from early cellular states.

Relapse and treatment resistance remain critical obstacles in the clinical management of angioimmunoblastic T-cell lymphoma (AITL), limiting the success of current therapeutic strategies. Therefore, a comprehensive characterization of the tumor microenvironment (TME) in AITL is essential to enhance treatment efficacy. This study analyzed samples from 68 patients with AITL, stratified into three molecular subtypes based on immunoglobulin (IG) gene rearrangement and flow cytometry results. Utilizing single-cell RNA sequencing, the TME was profiled across subtypes A, B, and C, sampling multiple disease sites including the bone marrow, lymph nodes, and peripheral blood. Our findings revealed subtype-specific variations in cellular composition and transcriptional programs within the TME. Unlike other subtypes, subtype C was associated with a pronounced immunosuppressive environment at diagnosis and relapse. Additionally, it exhibited an enhanced response to Epstein-Barr virus infection, consistent with upregulated CD70 expression at relapse. Through the analysis of cellular communication networks, CD70, programmed cell death 1 (PDCD1), and inducible T cell costimulator (ICOS) were identified as promising immunotherapeutic targets in AITL. Finally, we delineated distinct cellular proportions and gene expression signatures characteristic of each subtype, providing a foundation for the development of tailored therapeutic interventions for patients with AITL.

Aging is the leading risk factor for cognitive impairment and neurodegeneration, yet molecular changes that unfold in the brain over time, and how they drive this vulnerability, remain unclear. The naturally short-lived African turquoise killifish (Nothobranchius furzeri) offers a powerful model to understand brain aging on an accelerated timescale and test the impact of potential interventions. Here, we present a multi-omic atlas of brain aging of female and male African turquoise killifish from 2 independent genetic strains of different captive lifespans, encompassing single-nuclei RNA-seq, single nuclei ATAC-seq, and bulk ATAC-seq to capture transcriptional and regulatory changes. Interestingly, our atlas indicates that aging leads to a significant expansion of microglia numbers, regardless of sex or strain, which we independently validate using in-situ hybridization. In addition, we identify robust and conserved gene regulation changes, that are consistent with activation of glucocorticoid signalling as a hallmark (and potential driver) of vertebrate brain aging. Furthermore, pharmacological inhibition of glucocorticoid receptor activity starting at middle-age led to significant rescue of key molecular and cellular aging phenotypes. Thus, our study provides a powerful resource and framework to leverage the African turquoise killifish and rapidly uncover actionable pathways driving brain aging.

Human cytomegalovirus (CMV) is a globally widespread pathogen associated with significant morbidity in immunocompromised individuals. Despite its clinical importance, no licensed vaccine is currently available. This study aimed to design a rational multi-epitope vaccine candidate targeting CMV using an integrative approach combining immunoinformatics and structural biology. Viral proteins were screened to identify epitopes with high affinity for B cells, cytotoxic T cells (CTLs), and helper T cells (HTLs) using the Immune Epitope Database (IEDB). Selected epitopes were filtered according to their antigenicity and toxicity and then assembled into a chimeric construct incorporating an immunostimulatory adjuvant. The designed vaccine was evaluated for its physicochemical properties, validated by Ramchandran and ERRAT analyses. Molecular modeling demonstrated strong and stable interactions with key innate immunity receptors, including TLR7 and TLR9, interactions confirmed by molecular dynamics simulations. In silico immune simulation predicted a robust and durable immune response, characterized by high levels of IgM and IgG, as well as significant activation of CD4 + and CD8 + lymphocytes and innate immunity components. These results highlight the potential of the proposed multi-epitope construct as a promising vaccine candidate against HCMV. However, experimental validation is essential to confirm its immunogenicity, safety, and translational applicability.

The β2-adrenergic receptor (β2AR), a pivotal member of the G protein-coupled receptor (GPCR) family, plays a crucial role in cellular signaling and is extensively involved in many physiological and pathological processes. Unlike the classical β1AR, the β2AR exhibits unique biased signaling properties. Selective activation of specific downstream pathways, such as the β-arrestin pathway, ERK1/2, and PI3K/Akt, is mediated by ligand binding via biased signaling by a specific G protein, resulting in distinct cellular responses. This review provides an in-depth analysis of the complex mechanisms governing biased β2AR-mediated signaling, highlighting its crucial roles in cardiovascular health, respiratory pathologies, neuroregulatory mechanisms, immunological regulation, and tumor biology. Although β2AR-biased signaling is a well-established phenomenon, its underlying mechanisms and pathophysiological implications remain incompletely elucidated compared with traditional signaling modes. This paper summarizes recent studies on the specificity of β2AR signaling and examines its potential therapeutic applications. Future research should concentrate on clarifying the structural foundations of biased signaling, developing biased ligands, and using these discoveries for precision therapeutics. The therapeutic potential of β2AR-biased signaling is being fully explored, which may open new avenues for personalized treatment of various diseases and bring breakthroughs to the field of clinical medicine.

DFT calculations are increasingly combined with molecular docking to rank drug candidates, yet most studies report the interaction energy (ΔEint), computed at the complex geometry, as a surrogate for binding affinity. This quantity omits the deformation energy (ΔEdef): the thermodynamic penalty of distorting both partners from their free-state geometries into their bound conformations. Because ΔEdef is always positive (typically 2-20 kcal mol-1) and molecule-dependent, its omission systematically overestimates binding strength and can reverse predicted rank-orderings. We present the energetic decomposition ΔEbind = ΔEint + ΔEdef, demonstrate using published crystallographic strain data from over 3,000 protein-ligand complexes that deformation energies do not cancel between structurally distinct ligands, and propose a minimal five-step correction protocol applicable to any DFT-based drug design study. The protocol requires only two additional geometry optimizations beyond the standard workflow, adding only modest additional computational cost. This work does not introduce new computational data; it highlights an energetic inconsistency in common computational practice and provides a straightforward correction to enable more consistent electronic binding energy evaluation and improved candidate comparison.  METHODS: The analysis is based on the supramolecular energy decomposition framework and the activation strain model (ASM), in which binding energy is partitioned into interaction and deformation (strain) components using standard variational principles. No new DFT calculations are reported. The argument draws on published conformational strain datasets obtained at various DFT levels and molecular mechanics force fields from crystallographic analyses of the PDBBind database. The proposed correction protocol is general and can be applied with any DFT functional, basis set, and quantum chemistry software package (e.g., Gaussian, ORCA, or equivalent).

Pancreatic beta cells contain insulin secretory granules (ISGs), organelles where proinsulin is converted into insulin. As ISGs mature, they undergo extensive biophysical remodeling, producing a spectrum of subpopulations with heterogeneous molecular and spatial characteristics. However, systematic methods to define ISG subpopulations remain underdeveloped. To address this gap in knowledge, we employed soft X-ray tomography (SXT), which can quantitatively measure the biochemical density of ISGs within whole beta cells. Using unsupervised clustering, we classified subpopulations based on molecular density, size, and spatial positioning. Across different insulin secretory stimuli, we observed shifts toward mature and releasable subtypes, demonstrating that exogenous signals can dynamically remodel ISG subpopulation distributions. We extended this methodology to primary beta cells characterized using volume electron microscopy (vEM). Integrating subpopulations from SXT and vEM uncovered insights inaccessible by a single method in isolation. This strategy establishes a framework for defining therapeutic approaches aimed at enriching physiologically beneficial ISG subpopulations.

Malaria is a devastating disease that resulted in an estimated 610,000 deaths in 2024, the majority being children under the age of five. Here, we use KNX-115 to illustrate multistage antiparasitic activity upon targeting the cytoskeletal enzyme Plasmodium falciparum myosin A (PfMyoA). KNX-115 inhibits purified actin-activated ATPase with a potency in the low nanomolar range and >50-fold selectivity against cardiac, skeletal, and smooth muscle myosins. KNX-115 traps PfMyoA in a state that binds weakly to actin. A 2.35 Å resolution structure of KNX-115 bound to PfMyoA reveals critical interactions contributing to its mechanism of action. Importantly, in vitro evolution data reveal that KNX-115 engages PfMyoA as a sole cellular target. Inhibiting PfMyoA blocks the development of the blood and liver stages of laboratory strains of P. falciparum, with no liver cell toxicity, sporozoite cell traversal and motility, and sporozoite development in the mosquito. Inhibiting PfMyoA completely kills parasites after 96 h of treatment. Furthermore, KNX-115 is equally effective at inhibiting a panel of Plasmodium strains resistant to experimental and marketed antimalarials and shows inhibitory activity against P. falciparum circulating isolates from the Brazilian Amazon. Inhibiting PfMyoA with KNX-115 also blocks the blood stage of a laboratory strain of Plasmodium vivax. In line with the evolutionary identity of MyoA among various apicomplexan parasites, KNX-115 also inhibits Cryptosporidium and Eimeria MyoA in vitro and is an effective inhibitor of Cryptosporidium, Toxoplasma, and Eimeria cellular growth, with EC50s similar to those found for blood and liver stage Plasmodium.

A class of organic, naturally occurring compounds known as phytohormones affects physiological functions in plants at trace levels. Phytohormones play important roles in plant growth, development, nutrient transport, and survival by regulating plant responses to abiotic stress and form the basis of ability of plants for adapting to changing conditions. To carry out some specific and distinct functions, cells of complex organisms implement gene regulation dynamics according to their cell types, including during the synthesis and control of various plant hormones. Rather than the traditional approaches for phytohormone quantification, single-cell RNA sequencing (scRNA-seq) and/or single-nucleus RNA sequencing (snRNA-seq) technologies that enable high-resolution mapping of cellular heterogeneity at the transcriptomic level, provide a novel approach for the phytohormone signaling. Here, we detailed the methodology of single cell/nucleus technologies to investigate underlying gene regulatory networks of plant hormone biology.

RBMXL3 is a primate-specific gene localized on the X chromosome, of which the expression is detectable mainly in the male gonad. So far, very little is known about the RBMXL3 protein function and its molecular interactions. However, recent reports mention the RBMXL3 gene in the context of human spermatogenesis, cancer, and a breathing disorder that affects newborns. In this study, we investigate the RBMXL3's molecular network on a genome-wide scale using the human seminoma cell line (TCam-2) as a male germline in vitro model. By using transcriptomic (RNA sequencing [RNA-seq] and enhanced crosslinking and immunoprecipitation [eCLIP]) and proteomic (co-immunoprecipitation coupled with mass spectrometry, (Co-IP-MS)) approaches, we show RBMXL3's importance in RNA metabolism. In addition, western blot, quantitative polymerase chain reaction with reverse transcription (qRT-PCR), immunostaining, and confocal imaging were used to investigate the function of RBMXL3. Finally, we used a plasmid-based L1 retrotransposition assay to demonstrate the suppressive effect of RBMXL3 on human Long Interspersed Nuclear Element-1 (LINE-1, L1) retrotransposition. Our RNA-seq data show that RBMXL3 expression drives gene expression changes and influence alternative splicing in human cells. Moreover, by performing eCLIP, we provide proof that RBMXL3 binds to a wide range of RNA transcripts. In addition, we confirmed the nuclear localization of RBMXL3 in TCam-2 cells and its presence in spermatogonia and spermatocytes within the human testis. Finally, we report for the first time that RBMXL3 restricts human LINE-1 retrotransposition. Our findings for the first time identify primate-specific RBMXL3 protein as a new upstream regulator of RNA metabolism, characterized by broad RNA-binding activity in human TCam-2 cells. Finally, we show that RBMXL3 expression heavily reduces LINE-1 retrotransposition in human cells, underlying RBMXL3 importance in maintaining genome integrity. Our data suggest that RBMXL3 may contribute to the regulation of transcriptome dynamics in male germ cells, while its broader functional implications remain to be determined.

Triammonium citrate (TAC) is a citrate salt widely utilized in diverse industrial and dietary applications, leading to widespread human exposure. While related citrate salts have established safety profiles, the specific genotoxic potential and molecular interactions of TAC remain largely unexplored. This study provides the first integrated in vitro and in silico mechanistic safety assessment of TAC. Cell viability, evaluated in NIH/3T3 and MCF-7 cells via the CCK-8 assay, remained above 90% at all tested concentrations (0.25-2 mg/mL). Furthermore, a comprehensive genotoxicity battery-including the Ames test, chromosomal aberration, micronucleus, and sister chromatid exchange assays in human lymphocytes-revealed no mutagenic, clastogenic, or aneugenic activity. Beyond its safety profile, TAC exhibited marked chemoprotective activity, preserving supercoiled plasmid DNA with up to 96% protection against H₂O₂-induced oxidative damage. Molecular docking studies substantiated these findings by predicting moderate binding affinities for DNA replication enzymes (DNA polymerase δ: ΔG = -5.7 kcal/mol; topoisomerase I: ΔG = -5.9 kcal/mol) while showing a preferential affinity for the metabolic enzyme glutamine synthetase (ΔG = -6.1 kcal/mol). These in silico results suggest that TAC does not interfere with critical DNA maintenance machinery. Collectively, these findings establish a robust safety profile for TAC and unveil a previously unrecognized, antioxidant-mediated DNA-protective function, highlighting its potential as a bioactive functional ingredient capable of mitigating oxidative DNA stress.

Cluster of differentiation 38 (CD38) is a multifunctional ectoenzyme regulating immune functions, calcium signaling, and nicotinamide adenine dinucleotide (NAD+) metabolism. Through rapid hydrolytic degradation of NAD+, CD38 drives cellular NAD+ depletion during aging, inflammation, and tumor growth, contributing to mitochondrial dysfunction and immune suppression. Consequently, CD38 inhibition has been emerging as a potential approach for disease control by restoring NAD+ homeostasis and immunometabolic balance. This review summarizes current advances in the development of small-molecule CD38 inhibitors. Mechanism-based nucleotides and nucleosides enable potent inhibition of CD38 in a covalent manner. From NAD+ analogues and synthetic molecules to natural products, non-covalent inhibitors represent versatile strategies for elevating tissue NAD+ levels with great efficacy by blocking CD38 catalysis. These discoveries establish a diverse chemical landscape for CD38 modulation and provide tools for studying CD38 biology as well as insight into the identification of therapeutic candidates with promising pharmacological activities.

Chronic rhinosinusitis (CRS) is an inflammatory disorder of the sinonasal mucosa that occurs with or without nasal polyps (NPs). Compared with CRS without NPs, CRS with NPs (CRSwNP) is associated with more severe and uncontrolled sinonasal symptoms. Type 2 inflammation, driven by TH2 cytokines (interleukins 4, 5, and 13), promotes eosinophilic infiltration into NPs and contributes to disease progression and recurrence. Although recent studies have emphasized biological phenotyping and identified genetic/epigenetic endotypes to optimize treatment strategies for CRSwNP, clinical translation remains limited. Because cellular phenotypes are strongly influenced by metabolic alterations, profiling of the metabolic landscape may provide insight into CRSwNP pathogenesis and identify bio-markers of type 2 inflammationâ€"related symptom exacerbation, treatment resistance, and recurrence. However, metabolomic characterization of CRSwNP remains underexplored.

Death receptors (DRs) are a subset of the tumor necrosis factor receptor (TNFR) superfamily with a protein interaction motif called the death domain. DRs, particularly TNFR1, FAS and TRAIL-Rs, mediate critical cellular outcomes, including apoptosis, necroptosis, inflammation, survival, and proliferation. Phosphorylation is a rapid, reversible post-translational modification, and therefore might alter the downstream fate decisions in signal transduction pathways. Like most cytokines, death ligands activate a wide range of tyrosine kinases. However, our understanding of whether these tyrosine kinases phosphorylate DRs and modulate downstream signaling is limited. Depending on the cell type, several different tyrosine kinases, including Src family members, JAKs and EGFR have been demonstrated to be activated upon death ligand exposure. All three of these kinase families have the potential to phosphorylate DRs, as reviewed here, and these phosphorylation events create a bias towards proinflammatory and proliferative pathways over cell death. Since these kinases are frequently hyperactivated in cancer, this bias may sustain tumor cell survival and resistance to death receptor-targeted therapies, marking the responsible kinases and their opposing phosphatases as candidate therapeutic targets.