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