Cell Rep Med. 2026 Apr 10:102741. doi: 10.1016/j.xcrm.2026.102741. Online ahead of print.

ABSTRACT

Combined small-cell lung cancer (cSCLC) is an aggressive subtype of SCLC with mixed histologic components. Despite heterogeneity and poorer prognosis than de novo SCLC, cSCLC is managed as SCLC because molecular insight into biology, lineage plasticity, and tumor microenvironment (TME) is limited. We perform spatial whole-exome sequencing, spatial transcriptomics, and single-nucleus RNA sequencing across 19 treatment-naive cSCLC tumors. Different histologic components share a monoclonal origin, whereas divergence associates with distinct mutation and copy-number alteration patterns. Our results define spatially exclusive or interspersed tumor domains with distinct TME and immune landscapes; fibroblast-rich boundaries enriched for an aggressive fibroblast subtype may shape TME and treatment responses. We identify lineage plasticity, including adenocarcinoma-to-SCLC transdifferentiation and SCLC-subtype coexistence, and develop cSCLC Detector, a sensitive mutation-based assay improving cSCLC detection in tissue and liquid biopsies. These findings illuminate cSCLC evolution and heterogeneity, underscoring the need for tailored diagnostic and therapeutic strategies for this aggressive subtype.

PMID:41966692 | DOI:10.1016/j.xcrm.2026.102741

Commun Biol. 2026 Apr 11. doi: 10.1038/s42003-026-10033-1. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a complex disease without clear etiology or effective therapy. While DNA methylation has been implicated in IPF pathogenesis, the tissue-specific causal effects of the epigenetic factors on IPF remain undetermined. Here, we perform epigenome-wide Mendelian randomization using blood-based methylation quantitative trait loci of 420,509 CpG sites and genome-wide association study for IPF to elucidate the causal effects of the CpG sites on IPF. Totally, 452 CpG sites has shown putative causal effects on IPF risk after Bonferroni correction. Among them, 13 CpG sites have shown strong colocalization evidence with genetic factors associated with IPF. Specifically, DNA methylation at CpG sites within MAN2A2 and TRIM27 shows significant differences between IPF lungs and controls, correlating with altered mRNA expressions of these genes in lung tissues. The CpG site in MAN2A2 is a binding site of ZNF384 according to transcription factor databases. RNA sequencing in the TGFβ1-induced alveolar epithelia confirms significantly reduced expression of MAN2A2 and ZNF384 comparing to the controls. Collectively, our study suggests a putative causal link between DNA methylation within MAN2A2 and IPF risk, wherein lung-specific DNA methylation in MAN2A2 may perturb the interaction between ZNF384 and MAN2A2, revealing novel roles for these genes in IPF pathogenesis.

PMID:41965819 | DOI:10.1038/s42003-026-10033-1

J Transl Med. 2026 Apr 10;24(1):488. doi: 10.1186/s12967-026-07750-w.

NO ABSTRACT

PMID:41963995 | PMC:PMC13067594 | DOI:10.1186/s12967-026-07750-w

NPJ Syst Biol Appl. 2026 Apr 10. doi: 10.1038/s41540-026-00697-0. Online ahead of print.

ABSTRACT

The extracellular matrix (ECM) critically shapes tumor fate and treatment outcome, serving as a potent prognostic factor. Yet, its compositional heterogeneity across tumors makes it difficult to assess its impact on tumor dynamics. To address this, we introduce an ECM-guided patient stratification pipeline through integration of multi-omic data in lung cancer patients. We obtained four patient groups, representing ECM-grades that showed distinct clinical features, mutation profiles, and cellular heterogeneity. Investigation of patient-specific ECM-induced intracellular signaling via network modeling revealed strong enrichment of pathways and transcriptional regulators related to epithelial-mesenchymal transition (EMT) and cancer stemness in higher ECM-grades. Drug proximity analysis on ECM-grade specific networks predicted olaparib as an ECM-grade dependent therapeutic while erlotinib to be ECM-insensitive which were validated experimentally on lung tumor cells with distinct mutational profiles in response to differing ECM microenvironments. Overall, our ECM-mediated stratification approach is a robust system for capturing ECM heterogeneity and identifying patient groups that can be selectively targeted by distinct therapeutic strategies.

PMID:41963365 | DOI:10.1038/s41540-026-00697-0

Front Immunol. 2026 Mar 24;17:1796926. doi: 10.3389/fimmu.2026.1796926. eCollection 2026.

ABSTRACT

BACKGROUND: Pulmonary immune homeostasis requires tight control of adaptive responses. Integrin β3 is a well-known mediator of cell adhesion and platelet function. However, its role in adaptive immunity, especially in B cell responses, remains unclear.

METHODS: We defined the pulmonary phenotype of constitutive β3-deficient (β3^-/-) mice by histopathology. We performed integrated transcriptomic and proteomic profiling of lung tissue to map the molecular signature of spontaneous pulmonary inflammation. We further probed the underlying mechanisms with additional histology and functional assays and tested for biological significance using transcriptomics data from auto-immune disease patients.

RESULTS: β3^-/- mice developed spontaneous pulmonary inflammation marked by B cell activation and in situ immune-complex deposition within alveoli. Multi-omics integration implicated the CD40-CD40 Ligand (CD40L) axis as a central driver of this pathology. Mechanistically, loss of β3 enhanced CD40L-CD40 engagement on B cells, resulting in NF-κB pathway hyperactivation. Consistent with our murine data, reduced ITGB3 expression in patients with autoimmune disease correlated with transcriptional signatures of B cell activation and inflammation.

CONCLUSIONS: These results reframe integrin β3 as a threshold regulator of B cell activation. The β3-CD40L-CD40 axis therefore represents a potential therapeutic target for B cell-mediated autoimmune diseases.

PMID:41953039 | PMC:PMC13055533 | DOI:10.3389/fimmu.2026.1796926

BMC Med. 2026 Apr 8. doi: 10.1186/s12916-026-04833-9. Online ahead of print.

ABSTRACT

Immunosenescence, the age-related decline in immune function, plays a crucial role in the pathogenesis and progression of lung diseases, including chronic obstructive pulmonary disease, lung cancer, pulmonary fibrosis, asthma, and respiratory tract infections. This comprehensive review examines the hallmarks of immunosenescence, and illustrates the association between immunosenescence and the pathogenesis of lung diseases. In addition, we discuss current and emerging therapeutic strategies that have been evaluated in human clinical trials for targeting immunosenescence in lung diseases. Specifically, this review provides in-depth insights into the therapeutic strategies, including senolytics and senomorphics, immunotherapy, stem cell therapy, thymic rejuvenation, probiotics, and lifestyle. We also highlight the potential of personalized approaches integrating multi-omics data and artificial intelligence to guide biomarker-driven interventions, enabling truly personalized therapeutic strategies. Finally, this review underscores the imperative for rigorously designed clinical trials to develop and validate interventions that specifically target immunosenescence, with the ultimate goal of improving clinical outcomes for the aged population with lung diseases.

PMID:41952158 | DOI:10.1186/s12916-026-04833-9

Eur Respir Rev. 2026 Apr 8;35(180):250227. doi: 10.1183/16000617.0227-2025. Print 2026 Apr.

ABSTRACT

Pulmonary fibrosis (PF), the irreversible scarring of the lungs in many interstitial lung diseases, remains fatal despite currently approved antifibrotic therapy. Converging evidence shows that dysregulated innate and adaptive immunity orchestrates every stage of the fibrotic cascade. Roughly 20% of PF susceptibility loci map to immune regulatory genes, including Toll-interacting protein, interleukin (IL)-1 receptor antagonist, Toll-like receptor-3, complement receptor-1 and tumour necrosis factor-α (TNF-α), indicating that genetically primed host defence pathways predispose to maladaptive repair. Recurrent epithelial injury triggers a type 1 inflammatory response that gradually shifts toward type 2-skewed wound healing; the resulting cytokine milieu rich in transforming growth factor-β, IL-13, IL-6 and platelet-derived growth factor reprogrammes fibroblasts into collagen-secreting myofibroblasts. Spatial-omic profiling of PF lungs corroborates this model, revealing niches where profibrotic macrophages, T-helper cells and inflammatory fibroblasts colocalise within a stiff, collagen-rich matrix. Beyond their direct antimesenchymal actions, the current therapeutics pirfenidone and nintedanib also temper innate and adaptive immune signalling. Proof of concept for sharper immunomodulation now comes from recent phase III trials of nerandomilast, a highly selective phosphodiesterase-4B inhibitor that preserved forced vital capacity and downregulated TNF-α, IL-6 and IL-17 networks. These results demonstrate that immune pathway modulation can complement existing antifibrotics and invigorate efforts to align mechanism-based therapies with patient-specific immune endotypes, steered by genetics, cellular phenotypes and circulating biomarkers. This review synthesises current understanding of how immunity initiates, amplifies and perpetuates PF, linking genetic and mechanistic insights to emerging therapeutic opportunities. A deeper grasp of immune-epithelial-fibroblast crosstalk is essential for transforming disease-slowing care into genuinely disease-modifying intervention.

PMID:41951242 | PMC:PMC13058739 | DOI:10.1183/16000617.0227-2025

J Ethnopharmacol. 2026 Apr 6:121628. doi: 10.1016/j.jep.2026.121628. Online ahead of print.

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Chuanminshen violaceum Sheh et Shan is a medicinal-and-edible Apiaceae plant in China recorded for yin nourishment, lung/spleen tonification, and phlegm resolution, and used for cough and chronic respiratory complaints.

STUDY AIM: To synthesize current evidence on botanical resources, chemistry, pharmacology, and applications of C. violaceum, and to define priorities for standardized and safe development.

MATERIALS AND METHODS: This review integrates studies on resource distribution and ecological adaptability, multi-fraction phytochemistry, extraction-purification and formulation technologies, preclinical pharmacology, and quality, safety, and regulatory considerations.

RESULTS: C. violaceum contains structurally diverse polysaccharides plus volatile oils (often polyacetylene-rich), phenolics (e.g., chlorogenic acid and rutin), PUFA-rich lipids, and newly reported minor constituents. Polysaccharides show variable monosaccharide profiles, molecular-weight ranges, and linkage/branching patterns, strongly influenced by extraction-purification; derivatization (e.g., sulfation/selenization) and delivery systems can further tune physicochemical properties. Preclinical studies report antioxidant, anti-inflammatory, immunomodulatory, cardioprotective, and antiviral effects, commonly linked to Nrf2/Keap1 redox defense, inflammatory signaling control, TLR2/4-related immune regulation, gut-barrier reinforcement with microbiota remodeling, and anti-ferroptotic protection in myocardial ischemia-reperfusion models. Applications span traditional dosage forms and functional foods, but translation is limited by origin/process variability, incomplete long-term safety and ADME data, and regulatory uncertainty.

CONCLUSIONS: C. violaceum is a promising ethnomedicinal resource with clear part-specific features and polysaccharide-centered potential. Future work should combine multi-omics with target validation, fingerprint-guided QC and traceability, greener scalable processing, and regulatory-aligned safety packages to enable reproducible products.

PMID:41951195 | DOI:10.1016/j.jep.2026.121628

Front Genet. 2026 Mar 23;16:1722368. doi: 10.3389/fgene.2025.1722368. eCollection 2025.

ABSTRACT

Lung cancer is one of the most common cancers worldwide and one of the leading causes of cancer death, with a heavy disease burden and severe public health challenges. Multi-omics techniques, such as genomics, proteomics, metabolomics, and radiomics, play a crucial role in the early diagnosis and treatment of lung cancer, revealing the molecular characteristics and mechanisms of lung cancer, and have significant clinical application value. However, it also faces numerous challenges, such as data issues, "black box" problems, and ethical and legal concerns. How to leverage strengths while mitigating weaknesses, achieve clinical translation of technology, and serve patients more effectively deserves our deep reflection. This article reviews the specific applications and challenges of multi-omics methods in lung cancer research and personalized treatment.

PMID:41948518 | PMC:PMC13050793 | DOI:10.3389/fgene.2025.1722368

Front Immunol. 2026 Mar 23;17:1694651. doi: 10.3389/fimmu.2026.1694651. eCollection 2026.

ABSTRACT

INTRODUCTION: Fentanyl can rapidly impair brain and cardiopulmonary functions due to its high pharmacokinetics, necessitating a systems-level investigation to elucidate the early host response profile. To address this, we developed an SKH-1 mouse model to integrate ex-vivo imaging with multi-omics data, enabling a comprehensive understanding of tissue-specific host responses across time and dose gradients.

METHODS: Our previous study characterized the phenotypes of this mouse model to establish dose gradients and time points associated with major clinical manifestations. Building on these findings, cortex, heart, and lung tissues were collected postmortem at 40 min, 6h, 24h, and 7 days following administration of one of three fentanyl doses: the highest non-lethal dose (HNLD), LD10, and LD50.

RESULTS: Multi-omics analysis revealed immune response networks and apoptosis-necrosis functions as primary targets of fentanyl. Cortical and pulmonary immune responses exhibited dose-dependent latencies but remained activated 7 days post-exposure, whereas the cardiac immune response was suppressed over time. Pulmonary apoptosis-necrosis was rapidly activated, contrasting with its delayed, dose-dependent activation in the heart. In the cortex, apoptosis-necrosis followed a monophasic longitudinal trajectory, with delayed activation after 24h followed by regression. These findings suggest tissue-specific time windows for early intervention. Subsequent machine learning analysis identified phylogenetically conserved and miRNAs, such as miR-146-5p and miR-877-3p, which demonstrated consistent time- and dose-independent regulation in the lungs and cortex, respectively.

CONCLUSION: Functional associations of these miRNAs with tissue-specific lesions highlight their potential therapeutic value. Further interrogation of miRNA-mRNA interactions and downstream target analysis could pave the way for developing precision countermeasures against fentanyl toxicity.

PMID:41948326 | PMC:PMC13051511 | DOI:10.3389/fimmu.2026.1694651

Cytokine. 2026 Apr 6;202:157144. doi: 10.1016/j.cyto.2026.157144. Online ahead of print.

ABSTRACT

BACKGROUND: The remodeling of the tumor immune microenvironment (TME) is a pivotal determinant of therapeutic efficacy and clinical outcome in Lung Adenocarcinoma (LUAD). While WNT signaling is a known oncogenic driver, the specific immunomodulatory role of WNT7A and its potential crosstalk with inflammatory pathways in LUAD remain to be fully elucidated. We sought to define the prognostic value of WNT7A and explore the molecular mechanisms by which it may foster an immunosuppressive TME.

METHODS: We performed a multi-omics analysis utilizing the TCGA-LUAD cohort (N = 508) and validated findings in an independent external cohort (GSE30219, N = 293). The prognostic significance of WNT7A was evaluated using Kaplan-Meier and multivariate Cox regression analyses. TME composition was dissected via ssGSEA, focusing on myeloid-derived suppressor cell (MDSC) infiltration. Mechanistic pathways were identified using Gene Set Enrichment Analysis (GSEA) and gene co-expression networks.

RESULTS: High WNT7A expression was identified as a significant predictor of poor Overall Survival (OS) in the TCGA cohort (P < 0.05) and validated in the external cohort (P < 0.05). Multivariate analysis confirmed WNT7A as an independent prognostic risk factor (HR = 1.085, P = 0.036). Immunologically, WNT7A expression was positively correlated with MDSC infiltration (R = 0.43, P < 0.001), suggesting a shift towards an immune-tolerant phenotype. Mechanistically, GSEA revealed a robust activation of inflammatory signaling in the high-WNT7A group. Specifically, the TNFA Signaling via NF-κB pathway was significantly enriched(NES = 2.52, P < 0.001). Consistent with this pathway activation, WNT7A showed a statistically significant positive correlation with CCL2 (P < 0.001), a critical chemokine for MDSC recruitment, implicating the NF-κB/CCL2 axis in this process.

CONCLUSION: WNT7A serves as a prognostic biomarker linked to immune evasion in LUAD, potentially by modulating the NF-κB/CCL2/MDSC axis. This study identifies WNT7A as a potential therapeutic target to remodel the immune microenvironment, providing a rationale for future investigations into WNT-targeted strategies to improve immunotherapy efficacy.

PMID:41946008 | DOI:10.1016/j.cyto.2026.157144

J Ethnopharmacol. 2026 Apr 4:121650. doi: 10.1016/j.jep.2026.121650. Online ahead of print.

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Madeng'ai (MDA) is a traditional medicinal plant of the Dong ethnic group. Its roots have been widely used in folk medicine for clearing heat and removing toxins, alleviating swelling and relieving pain, dispersing blood stasis and arresting bleeding, as well as promoting wound healing. It is taxonomically classified as a variety of Potentilla freyniana Bornm.

AIM OF THE STUDY: Acute lung injury (ALI) is a life-threatening pulmonary disorder associated with high mortality, underscoring the urgent need to explore novel therapeutic strategies. This study aimed to evaluate the protective effects of the ethyl acetate fraction of MDA (MEA) against LPS-induced ALI in mice and to investigate its underlying mechanisms.

MATERIALS AND METHODS: LC-MS/MS was employed to tentatively identify the bioactive components of MEA. A mouse model of ALI was established by LPS induction. The protective effects of MEA were evaluated through assessments of lung histopathology, inflammatory cytokine levels, and oxidative stress markers. The underlying mechanisms were systematically investigated by integrating transcriptomics, metabolomics, network pharmacology, molecular docking, and Western blotting.

RESULTS: MEA significantly attenuated LPS-induced pulmonary pathological lesions, pulmonary edema, and excessive inflammatory responses in ALI mice. Comprehensive bioinformatics analyses predicted potential mechanisms involving oxidative stress and the regulation of metabolic pathways. Experimental validation via Western blotting confirmed that MEA inhibited TLR4-mediated inflammatory signaling and modulated the PI3K/AKT pathway, thereby exerting multi-pathway protective effects against ALI.

CONCLUSIONS: Collectively, this study confirms that MEA, as a traditional herbal extract, holds potential as an adjuvant therapeutic agent for ALI, providing experimental evidence for the modernization and development of ethnic medicines.

PMID:41941987 | DOI:10.1016/j.jep.2026.121650

iScience. 2026 Mar 11;29(4):115310. doi: 10.1016/j.isci.2026.115310. eCollection 2026 Apr 17.

ABSTRACT

Small cell lung cancer (SCLC) is a highly aggressive tumor with poor prognosis. Ferroptosis is closely linked to tumor antigen presentation: it affects antigen presentation efficiency via immunostimulatory signals, while CD8⁺ T cell activation induced by antigen presentation promotes tumor cell ferroptosis by secreting IFNγ. This study used multi-omics analyses and machine learning to screen key genes, verified by in vitro/in vivo experiments. TRIM36 and CAMK2N2 were significantly upregulated in SCLC, negatively correlating with patient survival, effector memory CD8⁺ T cell infiltration, and tumor MHC I expression. They suppress SCLC antigen presentation via ferroptosis-dependent/independent mechanisms, limiting T cell function. TRIM36 and CAMK2N2 are promising SCLC biomarkers and therapeutic targets, providing clues to unravel ferroptosis-antigen presentation associations in tumor cells and optimize immunotherapeutic strategies.

PMID:41940332 | PMC:PMC13049528 | DOI:10.1016/j.isci.2026.115310

Front Immunol. 2026 Mar 20;17:1787094. doi: 10.3389/fimmu.2026.1787094. eCollection 2026.

ABSTRACT

Pulmonary fibrosis (PF) significantly increases the risk of lung cancer (LC), but the mechanisms underlying this transition remain unclear. This overview positions macrophage heterogeneity as a central node within the PF-LC continuum. First, we describe important subpopulations of profibrotic and pro-tumor macrophages, including SPP1+, MERTK+, TREM2+, and MARCO+ cells, using high-resolution spatial and single-cell omics technologies. Next, we analyze the fundamental mechanisms that determine their function: the fibrotic microenvironment (e.g., extracellular matrix stiffness, hypoxia) induces profound metabolic reprogramming (e.g., Warburg effect, lipid peroxidation) and stabilizes epigenetic memory (e.g., DNA methylation, histone modifications), locking them into a pathogenic state. This reprogramming occurs through two main pathways: (1) metabolic reprogramming, characterized by aerobic glycolytic conversion and dysregulated lipid metabolism, which stimulates both pathogenic functions and suppression of T cell activity; (2) Epigenetic modifications, including stabilized alterations in DNA methylation, histone modifications, and superactivator patterns, which maintain cells in a tumor-promoting phenotype. As central nodes of communication, these macrophages interact pathologically with fibroblasts and epithelial cells through secreted factors and extracellular vesicles, forming self-reinforcing feedback loops that promote disease progression. We are studying the crucial role of new technologies, particularly multi-omic spatial models and high-precision organoids, in fostering mechanistic discoveries. These discoveries pave the way for new macrophage-focused therapeutic strategies, including the precise stratification of patients using biomarkers from liquid biopsies (such as soluble SPP1 and MARCO) and the development of targeted drug delivery systems for the selective modulation of macrophage function, thus establishing a new paradigm for therapeutic interventions in pulmonary fibrosis with concomitant lung cancer.

PMID:41939908 | PMC:PMC13046558 | DOI:10.3389/fimmu.2026.1787094

Front Immunol. 2026 Mar 19;17:1730289. doi: 10.3389/fimmu.2026.1730289. eCollection 2026.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease with limited treatment options and a poor prognosis. Recent studies suggest a critical role for the gut-immune-lung axis in IPF, yet the underlying molecular mechanisms remain unclear.

METHODS: The current study performed in silico multi-omics integration of publicly available datasets, including bulk RNA-seq, single-cell and spatial transcriptomics, as well as peripheral blood multi-omics data to uncover key molecular signatures in IPF. Furthermore, machine learning techniques were utilized to identify core genes, whereas functional analyses and Mendelian randomization were conducted to evaluate the causal relationships among gut microbiota, immune cells, and IPF. Additionally, experimental validation using qPCR and ELISA assays was conducted in vitro, in vivo, and in patient plasma to confirm the expression patterns of key genes.

RESULTS: Across integrated public bulk, single-cell, spatial, and blood multi-omics, CXCL13, IL33, TLR4, and IGF1 were identified as core IPF genes consistently linked to immune infiltration and fibrotic remodeling. Deconvolution, scRNA-seq, and spatial mapping localized their dysregulation to fibroblasts and immune compartments (notably B-cell, macrophage, and mast-cell axes), highlighting fibroblast-immune crosstalk in fibrotic foci. A four-gene model robustly distinguished IPF from controls across cohorts. Mendelian randomization supported a gut-immune-lung axis, indicating causal effects of specific gut taxa on IPF risk via immune phenotypes. qPCR/ELISA in TGF-β1-stimulated fibroblasts, bleomycin mouse lungs, and patient plasma corroborated upregulation of IL33, CXCL13, IGF1 and downregulation of TLR4. Drug-signature reversal nominated cucurbitacin I and temsirolimus; molecular docking was performed as a preliminary in silico, computer-simulation-based assessment of potential ligand-protein interactions between these compounds and the four core targets.

CONCLUSION: This study provides new insights into the importance of gut-immune-lung axis in IPF and identifies CXCL13, IL33, TLR4, and IGF1 as diagnostic signatures and therapeutic targets. By integrating public multi-omics resources with experimental validation, our findings offer a foundation for future diagnostic and treatment strategies aimed at modulating the gut microbiota and immune system in IPF.

PMID:41939867 | PMC:PMC13043422 | DOI:10.3389/fimmu.2026.1730289

Int J Med Sci. 2026 Mar 9;23(4):1408-1430. doi: 10.7150/ijms.128975. eCollection 2026.

ABSTRACT

Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality worldwide. Although the transcription-export (TREX) complex plays a central role in RNA maturation and nuclear export, the clinical and biological relevance of individual THO Complex Subunit (including THOC1, THOC2, THOC3, THOC5, THOC6, and THOC7) in LUAD is not well defined. We performed integrative analyses combining bulk transcriptomics from TCGA/GTEx and independent GEO cohorts, survival modeling, DNA methylation profiling, protein-level annotation from public resources, protein-protein interaction network analysis, immune infiltration estimation (TIMER), and single-cell RNA sequencing (scRNA-seq) to evaluate the relevance of THOC3 and THOC7 in LUAD. Across TCGA and external GEO validation datasets, THOC3 and THOC7 were consistently upregulated in LUAD and associated with poorer overall and disease-free survival, whereas other THO complex members showed weaker or inconsistent associations. Given these comparatively consistent and reproducible signals, we therefore prioritized THOC3 and THOC7 for downstream multi-layer analyses. Epigenetic profiling and interaction network analyses placed both genes within conserved RNA processing and export programs linked to genome maintenance pathways. Single-cell transcriptomic analysis provided additional resolution, demonstrating predominant enrichment of THOC3 and THOC7 in malignant epithelial clusters, with THOC3 aligning with transcriptional programs associated with DNA replication and repair, and THOC7 with proliferative and checkpoint-related states. Notably, expression of both genes was also detectable in myeloid and neutrophil subsets, and THOC7 expression remained elevated in recurrent LUAD samples, indicating association with aggressive and treatment-resistant disease states. Collectively, by integrating bulk, single-cell, epigenetic, and immune profiling across multiple independent cohorts, this study identifies THOC3 and THOC7 as reproducible molecular correlates of aggressive LUAD phenotypes. These highlight dysregulated RNA export programs as potential biomarkers of poor prognosis and motivate future functional studies to assess RNA export dependencies in LUAD.

PMID:41938520 | PMC:PMC13048885 | DOI:10.7150/ijms.128975

Comb Chem High Throughput Screen. 2026 Mar 27. doi: 10.2174/0113862073445368260131002109. Online ahead of print.

ABSTRACT

INTRODUCTION/OBJECTIVE: Lung cancer is the leading cause of cancer-related mortality worldwide, and non-small cell lung cancer (NSCLC) accounts for the majority of cases. Alterations in metabolic activities play important roles in NSCLC development, wherein related genes and metabolites interact with each other, involving multiple forms.

METHODS: To comprehensively understand the pathogenic mechanisms and improve the performance of clinical early, precise diagnosis, this study proposed a data-driven approach for biomarker discovery based on U-centered distance correlation network (DCN) to investigate NSCLC metabolism-related reactions. In DCN, changes in molecular relationships during NSCLC initiation and progression are measured using the t-statistics of U-centered distance correlation for network construction, in which prospective warning signals representing NSCLC onset can be identified without human intervention. Additionally, the network construction criterion in DCN can precisely and effectively capture both linear and nonlinear molecular relationships in simple and biologically relevant manners.

RESULTS: DCN was successfully employed to analyze NSCLC metabolism-related metabolomics and genomics datasets. Statistical analyses confirmed that compared with other algorithms, the gene and metabolite biomarker panels identified by DCN provided more reliable diagnostic capabilities for clinical NSCLC detection. Biological analyses revealed that disturbed energy metabolism and lipid metabolism occurred during tumor cell proliferation and growth in NSCLC patients.

DISCUSSION: The gene ASPA and metabolite aspartic acid were significantly decreased in NSCLC samples, suggesting that the corresponding amino acid metabolic activities were intricately linked to NSCLC progression.

CONCLUSION: These findings demonstrated that DCN can further facilitate NSCLC studies to improve clinical outcomes in patients.

PMID:41937706 | DOI:10.2174/0113862073445368260131002109

Naunyn Schmiedebergs Arch Pharmacol. 2026 Apr 5. doi: 10.1007/s00210-026-05251-7. Online ahead of print.

ABSTRACT

Lung adenocarcinoma (LUAD) is one of the leading causes of cancer-related deaths worldwide, and its complex tumor microenvironment (TME) is a key barrier to treatment. PANoptosis is a novel programmed cell death mechanism that integrates features of pyroptosis, apoptosis, and necroptosis. However, its core regulatory network and cell specific role in LUAD are still unclear. This study integrated three LUAD transcriptome datasets, screened differentially expressed genes through bioinformatics analysis, and intersected with PANoptosis-related genes to construct a protein interaction network, using a combination of 113 machine learning algorithms to screen and validate core genes and using CIBERSORT and single-cell transcriptome data to analyze the spatial expression characteristics of immune cell infiltration and core genes. Finally, the intervention mechanism of core targets and ginsenosides was validated through molecular docking, immunohistochemistry, and cell experiments (CCK-8, Western Blot). Six core genes of LUAD PANoptosis, including IRF1, NLRP3, CASP1, TIMP1, S100A8, and TLR4, were identified in the study. Single-cell analysis revealed that these genes were significantly enriched in M2 macrophages. Functional enrichment indicates that they jointly regulate death- and inflammation-related pathways such as NF-κB signaling and NOD-like receptor signaling. In vitro experiments have confirmed that ginsenosides can induce PANoptosis, promote tumor cell death, or inhibit LUAD cell proliferation by upregulating the ZBP1/AIM2/RIPK3/CASP1 death complex and inhibiting the TLR4/NLRP3 survival signaling axis. This study systematically revealed a PANoptosis core gene network centered on M2 macrophages in LUAD, elucidating a new mechanism by which ginsenosides induce integrated cell death by regulating this network. This provides new potential targets and theoretical basis for the immunotherapy of LUAD and the development of traditional Chinese medicine monomers.

PMID:41935997 | DOI:10.1007/s00210-026-05251-7

Adv Sci (Weinh). 2026 Apr 3:e17640. doi: 10.1002/advs.202517640. Online ahead of print.

ABSTRACT

The embryonic coelomic mesothelium acts as a critical progenitor hub during mammalian organogenesis, undergoing epithelial-to-mesenchymal transition (EMT) to drive vascular growth and parenchymal development in visceral organs. A prominent example is the epicardium, which plays an essential role during heart development. The principles of gene regulation in the coelomic mesothelium remain poorly defined. Specifically, it is unclear how cis-regulatory elements, including enhancers, orchestrate the spatiotemporal patterns of gene expression required for mesothelial identity and function. Here, a multi-omic approach was used to identify trans- and cis-regulatory elements that regulate mesothelial gene expression in three organs: heart, lung, and pancreas. This analysis uncovers a cardiac-specific regulatory circuit in which the transcription factor (TF) TBX20 selectively activates epicardial enhancers to orchestrate essential developmental programs. In contrast, TF MAF orchestrates pan-mesothelial gene expression via conserved CREs, which are absent in non-mesothelial lineages. Our integrated genomic analysis reveals MAF as a central custodian of mesothelial identity, a role underscored by its negative correlation with EMT, evolutionary conservation, and dynamic regulatory activity throughout development. Our work establishes a foundational blueprint of the gene regulatory landscape governing the coelomic mesothelium, defining both conserved principles and organ-specific mechanisms of spatiotemporal gene expression during early mammalian development.

PMID:41933934 | DOI:10.1002/advs.202517640

Future Sci OA. 2026 Dec;12(1):2653101. doi: 10.1080/20565623.2026.2653101. Epub 2026 Apr 3.

ABSTRACT

BACKGROUND: Clarification of the molecular mechanism of malignant tumor progression, identification of the key signaling pathways and molecules involved in the processes of invasion and metastasis, and identification of new targets and strategies for effective tumor treatment are extremely important for scientific research and clinical application prospects.

METHODS: Based on large-sample data mining, we first evaluated the expression and mutation profiles of SPRR family genes across cancers and then focused on the molecular functions of SPRR2D across cancers.

RESULTS: Multi-omics experiments revealed that SPRR2D is significantly overexpressed in various tumors, especially in LUSC. ROC curve analysis revealed that SPRR2D demonstrated significant diagnostic efficacy across cancers. Cox regression analysis revealed that the expression of SPRR2D was associated with the survival time of patients with various tumors. Moreover, the expression of SPRR2D is closely related to tumor immune infiltration. GDSC data analysis revealed that the expression levels of SPRR1A, SPRR1B, SPRR2A, SPRR3, and SPRR2D are negatively correlated with the sensitivity to gefitinib, trametinib, bosutinib, afatinib, lapatinib, and erlotinib.

CONCLUSIONS: From a multi-omics perspective, it was revealed that SPRR2D plays a significant role in regulating tumorigenesis and drug sensitivity in tumors.

PMID:41933926 | PMC:PMC13051589 | DOI:10.1080/20565623.2026.2653101