Environ Int. 2026 Apr 8;210:110249. doi: 10.1016/j.envint.2026.110249. Online ahead of print.

ABSTRACT

BACKGROUND: Deoxynivalenol (DON), a prevalent food-borne mycotoxin, increasingly recognized as a potent driver in the progression of chronic liver disease to cirrhosis and hepatocellular carcinoma (HCC); however, its systematic role is unclear. This study aims to decode the pathogenic networks of DON through an integrated multi-omics and toxicological framework.

METHODS: We integrated transcriptomic datasets from public repositories (GSE139602 and GSE25097) and single-cell RNA-seq data (GSE136103 and GSE149614) with toxicogenomics data. Analytical approaches included differential expression analysis, protein-protein interaction networks, profiling, single-cell trajectory analysis, trend testing, and machine learning modeling, and molecular docking. Key findings were validated through in vitro assays in human hepatocytes (THLE-2), as well as in vivo mouse models.

RESULTS: Five core hub genes (FAT1, CCND1, FOS, GADD45G, and PHLDA1) were identified as consistent drivers of DON-induced liver injury progression. Longitudinal analysis revealed that FAT1 and CCND1 underwent progressive upregulation, while GADD45G, and PHLDA1 were significantly suppressed across disease stages. Molecular docking and Cellular Thermal Shift Assays (CETSA) provided physical evidence of direct binding between DON and these hub proteins. Furthermore, prolonged DON exposure induced significant G2/M phase arrest in hepatocytes, consistent with the sustained dysregulation of the GADD45G/CCND1 axis. In vivo results corroborated that DON triggers noticeable hepatic structural damage and inflammatory infiltration, synchronized with hub protein dysregulation.

CONCLUSION: Chronic DON exposure drives liver disease progression by dysregulating core molecular networks and direct interaction with key hub proteins. Our integrated approach provides novel mechanistic insights and highlights potential biomarkers for DON-induced hepatotoxicity.

PMID:41967175 | DOI:10.1016/j.envint.2026.110249

Pharmacol Res. 2026 Apr 9:108186. doi: 10.1016/j.phrs.2026.108186. Online ahead of print.

ABSTRACT

Community-acquired pneumonia (CAP) remains a major global public health challenge with substantial morbidity and mortality. Although preclinical studies suggest that Maxing Huoqiao (MXHQ) granule may have therapeutic potential for pneumonia, high-quality clinical evidence is still limited. We conducted a multicenter, double-blind, randomized, placebo-controlled trial at two tertiary hospitals in China to evaluate the clinical efficacy of MXHQ as adjunctive therapy and to explore its potential mechanisms in adults with nonsevere CAP receiving standard moxifloxacin treatment. A total of 96 patients were enrolled and randomized (1:1:1) to receive standard-dose MXHQ, low-dose MXHQ, or placebo in addition to moxifloxacin for 7 days, with a 14-day follow-up. The primary endpoint was clinical cure, defined as composite recovery of major respiratory symptoms, lung rales, and fever; secondary endpoints included symptom relief, radiographic improvement, and safety. Compared with placebo, standard-dose MXHQ was associated with a higher day-14 clinical cure rate (30.78% vs. 68.97%; RR = 0.45, 95% CI = 0.24-0.83; P < 0.01). Furthermore, the standard-dose intervention was correlated with a shorter time to relief and recovery of cough and sputum (P < 0.05), as well as improvements in symptom scores (P < 0.05) and promoting lesion absorption on chest CT (P < 0.05). Low-dose MXHQ showed no significant clinical benefit, whereas safety profiles were comparable across all groups. Transcriptomic analyses of peripheral blood mononuclear cells, complemented by a Streptococcus pneumonia animal model, indicated that the clinical benefits of MXHQ are linked to the modulation of inflammation and innate immunity. These omics and in vivo observations suggest a potential mechanism underlying the protective effects of MXHQ against inflammatory injury and promotion of tissue repair, involving the regulation of anti-inflammatory mediators and tissue repair-related factors. (Chictr.org.cn, ID Number: ChiCTR2400082095).

PMID:41966499 | DOI:10.1016/j.phrs.2026.108186

Gene. 2026 Apr 9:150160. doi: 10.1016/j.gene.2026.150160. Online ahead of print.

ABSTRACT

Porcine gastric epithelial cells (PGECs) serve as a valuable model for studying the molecular and pathogenic mechanisms of the stomach. However, PGECs face limitations such as isolation challenges, short lifespan, and restricted proliferation. To address this, we established an immortalized PGECs (i-PGECs) to enable in vitro investigation of pathogen infection mechanisms. Primary PGECs were isolated from the acid-secreting glands using stepwise digestion with multiple enzymes (dispase II/collagenase I/hyaluronidase). Immortalization was achieved via lentiviral vectors expressing simian virus 40 large T antigen (SV40T) and human telomerase reverse transcriptase (hTERT), with successful expression confirmed by qRT-PCR (P < 0.05). Epithelial identity of i-PGECs was confirmed by stable expression of CK18, EpCAM, and E-cadherin, as shown by qRT-PCR and immunofluorescence. i-PGECs retained the morphological and ultrastructural features of PGECs and exhibited enhanced proliferation, as demonstrated by WST-8 assays, apoptosis and cell cycle analysis, karyotyping, and transmission electron microscopy (TEM). Telomere length analysis and scratch wound assays demonstrated stable telomere maintenance and consistent migration capacity unaffected by passaging. RNA-sequencing and differential expressed genes (DEGs) analysis revealed significantly upregulating of genes involved in cell proliferation pathways (P < 0.01). Following aflatoxin B1 (AFB1) exposure, i-PGECs significantly upregulated immune-related factors, such as NPC1 and PLAUR (P < 0.01). CRISPR/Cas9-mediated knockout of NPC1 in i-PGECs conferred increased resistance to AFB1-induced cytotoxicity, as shown by WST-8 assay. The i-PGECs remained stable after more than 50 passages, supporting their use as a reliable for in vitro model investigating the mechanisms of toxicity infection in the porcine gastric epithelium.

PMID:41966285 | DOI:10.1016/j.gene.2026.150160

Environ Int. 2026 Apr 8;210:110249. doi: 10.1016/j.envint.2026.110249. Online ahead of print.

ABSTRACT

BACKGROUND: Deoxynivalenol (DON), a prevalent food-borne mycotoxin, increasingly recognized as a potent driver in the progression of chronic liver disease to cirrhosis and hepatocellular carcinoma (HCC); however, its systematic role is unclear. This study aims to decode the pathogenic networks of DON through an integrated multi-omics and toxicological framework.

METHODS: We integrated transcriptomic datasets from public repositories (GSE139602 and GSE25097) and single-cell RNA-seq data (GSE136103 and GSE149614) with toxicogenomics data. Analytical approaches included differential expression analysis, protein-protein interaction networks, profiling, single-cell trajectory analysis, trend testing, and machine learning modeling, and molecular docking. Key findings were validated through in vitro assays in human hepatocytes (THLE-2), as well as in vivo mouse models.

RESULTS: Five core hub genes (FAT1, CCND1, FOS, GADD45G, and PHLDA1) were identified as consistent drivers of DON-induced liver injury progression. Longitudinal analysis revealed that FAT1 and CCND1 underwent progressive upregulation, while GADD45G, and PHLDA1 were significantly suppressed across disease stages. Molecular docking and Cellular Thermal Shift Assays (CETSA) provided physical evidence of direct binding between DON and these hub proteins. Furthermore, prolonged DON exposure induced significant G2/M phase arrest in hepatocytes, consistent with the sustained dysregulation of the GADD45G/CCND1 axis. In vivo results corroborated that DON triggers noticeable hepatic structural damage and inflammatory infiltration, synchronized with hub protein dysregulation.

CONCLUSION: Chronic DON exposure drives liver disease progression by dysregulating core molecular networks and direct interaction with key hub proteins. Our integrated approach provides novel mechanistic insights and highlights potential biomarkers for DON-induced hepatotoxicity.

PMID:41967175 | DOI:10.1016/j.envint.2026.110249

bioRxiv [Preprint]. 2026 Mar 11:2026.03.09.710586. doi: 10.64898/2026.03.09.710586.

ABSTRACT

The lack of accurate, human-based models recapitulating early-stage pancreatic ductal adenocarcinoma (PDAC) has hindered therapeutic development. Using pluripotent stem cell-derived pancreatic progenitor organoids, we established a human PDAC model that faithfully reproduces the genetic, epigenetic, and transcriptomic trajectory of tumor initiation and progression in vitro , validated against clinical datasets and histopathology. We demonstrate that CDKN2A loss, nearly universal in patients but dispensable in mouse models, is essential for neoplastic transformation when combined with KRAS and TP53 mutations, while SMAD4 loss promotes tumor progression. Multi-omics profiling reveals epigenetic repression of pancreatic lineage program during PDAC initiation, alongside oncogenic AP-1-driven chromatin remodeling. Notably, we identify TET1 suppression as a mechanistic link between oncogenic ERK signaling and the hypermethylation and silencing of essential pancreatic transcription factors. This model captures the genetic and epigenetic determinants of human PDAC, reveals antagonism between oncogenic and lineage restriction programs, and supports TET-based lineage restoration as a promising early intervention strategy for high-risk individuals.

PMID:41959451 | PMC:PMC13060829 | DOI:10.64898/2026.03.09.710586

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

Immunity. 2026 Apr 8:S1074-7613(26)00075-0. doi: 10.1016/j.immuni.2026.02.005. Online ahead of print.

ABSTRACT

DNA mutations are a well-characterized source of neoepitopes in immunotherapy. Here, we examined the contribution of dysregulated RNA processing to neoantigen production. Leveraging multi-omics and checkpoint inhibitor (CPI) response data from >1,000 patients, we identified reduced activity of the nonsense-mediated mRNA decay (NMD) pathway kinase SMG1 as a predictor of improved CPI response. NMD inhibition through SMG1 targeting stabilized transcripts containing premature termination codons, most of which were of non-mutational origin. This reshaped the major histocompatibility complex class I (MHC class I)-bound immunopeptidome and increased neoantigen abundance to levels comparable to high mutation burden tumors. Functionally, NMD inhibition drove antigen-dependent T cell-mediated tumor cell killing in vitro, promoted activation of tissue-resident T cells in patient-derived models ex vivo, and improved CPI efficacy in vivo. Our findings establish NMD inhibition as a strategy to harness a previously inaccessible source of canonical and non-canonical neoantigens, with the potential to increase tumor immunogenicity across cancers.

PMID:41956098 | DOI:10.1016/j.immuni.2026.02.005

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

Acta Biochim Biophys Sin (Shanghai). 2026 Mar 25. doi: 10.3724/abbs.2025238. Online ahead of print.

ABSTRACT

The environmental pollutant benzo(a)pyrene (B(a)P), a representative polycyclic aromatic hydrocarbon (PAH), is a recognized carcinogen, and chronic pulmonary inflammation is closely associated with lung carcinogenesis. Although alveolar type 2 (AT2) cells are the origin of lung adenocarcinoma, the genetic and functional changes in AT2 cells and the mechanisms involved in inflammation-related lung tumorigenesis have not been elucidated. Here, C57BL/6J mice are exposed to B(a)P and the inflammatory irritant lipopolysaccharide (LPS) to establish a model of inflammation-related lung tumorigenesis. Single-cell RNA sequencing is performed on lung tissues. DNA mutations in AT2 cells are analyzed via whole-exome sequencing. The protein expression of AT2 cells in lung cancer tissue is determined by immunofluorescence staining. The results reveal that LPS promotes B(a)P-induced lung tumorigenesis; in the whole lungs of B(a)P/LPS, a decreased proportion, altered differentiation trajectory, and increased gene mutation number in AT2 cells are observed. Additionally, in B(a)P/LPS-treated lung cancer tissue, the levels of γ-H2AX DNA damage and the proliferation marker Ki67 in AT2 cells are increased, whereas the levels of differentiation markers are decreased. Single-cell RNA transcriptomics reveals that the autophagy-related genes Foxo3 and Ppp2r5, which are enriched in the PI3K-Akt pathway, and the autophagy-related genes in AT2 cells in lung cancer are decreased in the B(a)P/LPS group. Thus, chronic inflammation promotes DNA damage, gene mutation and dysfunction in AT2 cells, and decreased autophagy in AT2 cells may be an important mechanism for inflammation-related lung tumorigenesis.

PMID:41952558 | DOI:10.3724/abbs.2025238

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

JHEP Rep. 2026 Feb 18;8(5):101790. doi: 10.1016/j.jhepr.2026.101790. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) exhibits diverse aetiologies and molecular heterogeneity, with a median 5-year overall survival of <70% due to high recurrence rates following curative-intent surgery. This study investigated the complex tumour microenvironment (TME) in HCC and explored interactions between various cell types and their roles in disease recurrence.

METHODS: Using a multi-omics approach on multi-region samples of surgically resected HCC from the PLANet 1.0 cohort (NCT03267641), we performed spatial transcriptomics on 17 tissue samples from four patients and bulk RNA sequencing on 329 sectors from 90 patients. Findings were validated using immunofluorescence and multiplex immunohistochemistry.

RESULTS: Our analysis revealed extensive intra- and intertumour gene expression heterogeneity and identified a specific subset of endothelial cells (ECs), INTS6⁺ ECs, enriched and spatially colocalised with tumour cells in primary tumours from patients with recurrence (p = 0.021, n = 49). A significant ANGPTL4-SDC1 ligand-receptor interaction was identified between INTS6⁺ ECs and tumour cells. Notably, INTS6⁺ ECs were enriched in microvascular invasion regions and spatially colocalised with tumour cells in patients with recurrence (p = 0.036, n = 53). These findings highlight endothelial-tumour cell interactions within the TME as potential therapeutic targets.

CONCLUSIONS: INTS6⁺ ECs are enriched in microvascular invasion regions and spatially colocalised with tumour cells in recurrent HCC, suggesting a potential role in disease recurrence and representing a promising therapeutic target within the TME.

IMPACT AND IMPLICATIONS: The spatial co-localisation of cell types plays a significant role in the recurrence of hepatocellular carcinoma. In this study, we have pinpointed a particular group of endothelial cells, known as INTS6+ endothelial cells, which are spatially colocalised with tumour cells and enriched in microvascular invasion regions in patients experiencing recurrence. These discoveries highlight novel therapeutic targets that focus on endothelial cell interactions within the tumour microenvironment to prevent recurrence and enhance overall patient survival.

PMID:41950768 | DOI:10.1016/j.jhepr.2026.101790

JHEP Rep. 2026 Feb 18;8(5):101790. doi: 10.1016/j.jhepr.2026.101790. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) exhibits diverse aetiologies and molecular heterogeneity, with a median 5-year overall survival of <70% due to high recurrence rates following curative-intent surgery. This study investigated the complex tumour microenvironment (TME) in HCC and explored interactions between various cell types and their roles in disease recurrence.

METHODS: Using a multi-omics approach on multi-region samples of surgically resected HCC from the PLANet 1.0 cohort (NCT03267641), we performed spatial transcriptomics on 17 tissue samples from four patients and bulk RNA sequencing on 329 sectors from 90 patients. Findings were validated using immunofluorescence and multiplex immunohistochemistry.

RESULTS: Our analysis revealed extensive intra- and intertumour gene expression heterogeneity and identified a specific subset of endothelial cells (ECs), INTS6⁺ ECs, enriched and spatially colocalised with tumour cells in primary tumours from patients with recurrence (p = 0.021, n = 49). A significant ANGPTL4-SDC1 ligand-receptor interaction was identified between INTS6⁺ ECs and tumour cells. Notably, INTS6⁺ ECs were enriched in microvascular invasion regions and spatially colocalised with tumour cells in patients with recurrence (p = 0.036, n = 53). These findings highlight endothelial-tumour cell interactions within the TME as potential therapeutic targets.

CONCLUSIONS: INTS6⁺ ECs are enriched in microvascular invasion regions and spatially colocalised with tumour cells in recurrent HCC, suggesting a potential role in disease recurrence and representing a promising therapeutic target within the TME.

IMPACT AND IMPLICATIONS: The spatial co-localisation of cell types plays a significant role in the recurrence of hepatocellular carcinoma. In this study, we have pinpointed a particular group of endothelial cells, known as INTS6+ endothelial cells, which are spatially colocalised with tumour cells and enriched in microvascular invasion regions in patients experiencing recurrence. These discoveries highlight novel therapeutic targets that focus on endothelial cell interactions within the tumour microenvironment to prevent recurrence and enhance overall patient survival.

PMID:41950768 | DOI:10.1016/j.jhepr.2026.101790