Adv Sci (Weinh). 2026 May 26:e75839. doi: 10.1002/advs.75839. Online ahead of print.

ABSTRACT

Lung squamous cell carcinoma (LUSC) lacks clearly defined key drivers and effective targeted therapies, reflecting an incomplete understanding of its molecular pathogenesis. Here, we identify SMAD4 as a critical regulator of three-dimensional (3D) genome organization in LUSC and uncover a mechanistic link between tumor suppressor loss and oncogenic transcriptional activation. By integrating clinical datasets, genetically engineered mouse models, human and murine LUSC cell lines, and multi-omics analyses, we demonstrate that SMAD4 deficiency promotes LUSC progression by unleashing EP300-mediated enhancer-promoter looping at the SOX2 locus. Mechanistically, SMAD4 does not directly bind SOX2 regulatory elements but instead constrains chromatin looping by sequestering EP300 away from loop anchor regions. Loss of SMAD4 leads to enhanced H3K27ac deposition, aberrant SOX2 activation, and increased LUSC tumor cell proliferation. Together, these findings reveal a non-canonical role for a transcription factor (e.g., SMAD4) in regulating dysregulated 3D genome architecture to inhibit tumor development.

PMID:42189071 | DOI:10.1002/advs.75839

Adv Sci (Weinh). 2026 May 26:e75839. doi: 10.1002/advs.75839. Online ahead of print.

ABSTRACT

Lung squamous cell carcinoma (LUSC) lacks clearly defined key drivers and effective targeted therapies, reflecting an incomplete understanding of its molecular pathogenesis. Here, we identify SMAD4 as a critical regulator of three-dimensional (3D) genome organization in LUSC and uncover a mechanistic link between tumor suppressor loss and oncogenic transcriptional activation. By integrating clinical datasets, genetically engineered mouse models, human and murine LUSC cell lines, and multi-omics analyses, we demonstrate that SMAD4 deficiency promotes LUSC progression by unleashing EP300-mediated enhancer-promoter looping at the SOX2 locus. Mechanistically, SMAD4 does not directly bind SOX2 regulatory elements but instead constrains chromatin looping by sequestering EP300 away from loop anchor regions. Loss of SMAD4 leads to enhanced H3K27ac deposition, aberrant SOX2 activation, and increased LUSC tumor cell proliferation. Together, these findings reveal a non-canonical role for a transcription factor (e.g., SMAD4) in regulating dysregulated 3D genome architecture to inhibit tumor development.

PMID:42189071 | DOI:10.1002/advs.75839

Phytomedicine. 2026 May 15;157:158305. doi: 10.1016/j.phymed.2026.158305. Online ahead of print.

ABSTRACT

BACKGROUND: Severe acute pancreatitis (SAP) lacks targeted therapies, and massive loss of functional pancreatic acinar cells (PAC) drives mortality. Kaempferol (KA) possesses well-established anti-inflammatory and cytoprotective activities and is derived from herbal medicinal plants, but its direct molecular targets and mechanism of action in SAP remain undefined.

PURPOSE: To evaluate the protective effects of KA against SAP and to elucidate its molecular mechanism of specific action, with a focus on identifying the direct cellular target through which KA exerts its cytoprotective effects.

STUDY DESIGN: Gain‑/loss‑of‑function in vitro and PAC‑specific CD47 SAP mouse models, combined with multi‑omics screening and biophysical assays.

METHODS: CD47 manipulation (siRNA/overexpression) was performed in primary PACs and cell lines, combined with WT/CD47^-/-/Mist1‑CD47‑iOE (PAC‑specific) mouse models. Network pharmacology, transcriptomics and proteomics were integrated to screen and validate KA's protective effects. Computational‑experimental approaches (molecular docking/dynamics, CETSA, SPR, co‑IP, pharmacological epistasis) characterized KA's allosteric modulation of CD47 signaling.

RESULTS: CD47 was upregulated in SAP; its knockout reduced PAC death via KEAP1/PGAM5/AIFM1-driven oxeiptosis. KA reduced PAC death across genotypes, afforded no extra benefit in CD47-KO, and was not overridden by CD47‑OE. Mechanistically, KA allosterically binds CD47 ectodomain, stabilizes the CD47‑ UBQLN1 complex, and redirects signaling from Gαi‑mediated death to Gβγ/ ERK/NRF2‑mediated survival. ERK inhibition attenuated KA's protection. KA's action was CD47‑dependent.

CONCLUSION: This study identifies anti-oxeiptosis as a novel pharmacological activity of KA in SAP. This is achieved through allosteric modulation of CD47, redirecting its signaling from death‑promoting to a protective axis via activating Gβγ/ERK/NRF2 to suppress oxeiptosis. These findings reveal the CD47‑oxeiptosis axis as a therapeutic target and position KA as a promising candidate for SAP therapy, adding a new mechanistic dimension to KA's known pharmacological profile.

PMID:42184499 | DOI:10.1016/j.phymed.2026.158305

Front Immunol. 2026 May 8;17:1780459. doi: 10.3389/fimmu.2026.1780459. eCollection 2026.

ABSTRACT

Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and its ligand programmed death-ligand 1 (PD-L1) have transformed the management of advanced lung cancer, yet most patients experience primary resistance, hyperprogressive disease (HPD), or clinically significant immune-related adverse events (irAEs). Multi-omics technologies now enable integrated interrogation of tumor, microenvironmental, host, and clinical determinants of these divergent outcomes. In this review, we first discuss the biological and clinical foundations of PD-1/PD-L1 blockade in non-small cell and small cell lung cancer, and summarize the spectrum of resistance, HPD, and irAEs observed in trials and real-world practice. We then describe multi-omics study frameworks that connect genomics, transcriptomics, epigenomics, proteomics, metabolomics, radiomics, and microbiome profiling with these outcome phenotypes. Building on this foundation, we synthesize evidence for composite biomarkers of primary and acquired resistance, delineate emerging multi-omics signatures of HPD, and examine host- and tumor-derived multi-omics correlates of organ-specific and systemic irAEs. We further propose an efficacy-risk quadrant framework to guide clinical decision-making when favorable efficacy predictors coexist with elevated risk of severe adverse outcomes, and outline a three-step approach for high-efficacy/high-risk patients: joint probability reporting, multi-omics guided mitigation, and dynamic reassessment. Finally, we evaluate translational strategies that integrate multi-omics scores into baseline risk stratification, dynamic monitoring with attention to technical challenges such as distinguishing true progression from ctDNA pseudoprogression, and biomarker-driven trial design, while assessing the evidence level and translational readiness of candidate assays from retrospective discovery to clinical implementation. A clinical case illustrates how multi-omics can link baseline risk stratification, regimen selection, and longitudinal monitoring into a coherent action plan, while acknowledging that artificial intelligence-driven models remain investigational and real-world application still relies on clinician judgment. Collectively, this review defines how integrated multi-omics biomarkers can be leveraged to predict resistance, HPD, and immune-related toxicity, and to refine patient selection and management during PD-1/PD-L1 therapy in lung cancer.

PMID:42183274 | PMC:PMC13194140 | DOI:10.3389/fimmu.2026.1780459

Front Immunol. 2026 May 8;17:1780459. doi: 10.3389/fimmu.2026.1780459. eCollection 2026.

ABSTRACT

Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and its ligand programmed death-ligand 1 (PD-L1) have transformed the management of advanced lung cancer, yet most patients experience primary resistance, hyperprogressive disease (HPD), or clinically significant immune-related adverse events (irAEs). Multi-omics technologies now enable integrated interrogation of tumor, microenvironmental, host, and clinical determinants of these divergent outcomes. In this review, we first discuss the biological and clinical foundations of PD-1/PD-L1 blockade in non-small cell and small cell lung cancer, and summarize the spectrum of resistance, HPD, and irAEs observed in trials and real-world practice. We then describe multi-omics study frameworks that connect genomics, transcriptomics, epigenomics, proteomics, metabolomics, radiomics, and microbiome profiling with these outcome phenotypes. Building on this foundation, we synthesize evidence for composite biomarkers of primary and acquired resistance, delineate emerging multi-omics signatures of HPD, and examine host- and tumor-derived multi-omics correlates of organ-specific and systemic irAEs. We further propose an efficacy-risk quadrant framework to guide clinical decision-making when favorable efficacy predictors coexist with elevated risk of severe adverse outcomes, and outline a three-step approach for high-efficacy/high-risk patients: joint probability reporting, multi-omics guided mitigation, and dynamic reassessment. Finally, we evaluate translational strategies that integrate multi-omics scores into baseline risk stratification, dynamic monitoring with attention to technical challenges such as distinguishing true progression from ctDNA pseudoprogression, and biomarker-driven trial design, while assessing the evidence level and translational readiness of candidate assays from retrospective discovery to clinical implementation. A clinical case illustrates how multi-omics can link baseline risk stratification, regimen selection, and longitudinal monitoring into a coherent action plan, while acknowledging that artificial intelligence-driven models remain investigational and real-world application still relies on clinician judgment. Collectively, this review defines how integrated multi-omics biomarkers can be leveraged to predict resistance, HPD, and immune-related toxicity, and to refine patient selection and management during PD-1/PD-L1 therapy in lung cancer.

PMID:42183274 | PMC:PMC13194140 | DOI:10.3389/fimmu.2026.1780459

Dev Cell. 2026 May 19:S1534-5807(26)00159-0. doi: 10.1016/j.devcel.2026.04.012. Online ahead of print.

ABSTRACT

The lack of accurate human models that recapitulate pancreatic ductal adenocarcinoma (PDAC) initiation 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 trajectories of tumor initiation and progression, validated against clinical datasets and tumor histopathology. We demonstrate that CDKN2A loss, which is nearly universal in patients but dispensable in mouse models, is essential for neoplastic transformation when combined with KRAS and TP53 mutations, whereas SMAD4 loss promotes tumor progression. Multi-omics profiling reveals epigenetic repression of the pancreatic lineage program during PDAC initiation, alongside AP-1-driven chromatin remodeling. We identify TET1 suppression as a mechanistic link between oncogenic ERK signaling and hypermethylation of essential pancreatic transcription factors. This model captures genetic and epigenetic determinants of human PDAC, reveals antagonism between oncogenic and lineage restriction programs, and supports TET-based lineage restoration as a potential early intervention strategy.

PMID:42161274 | PMC:PMC13196429 | DOI:10.1016/j.devcel.2026.04.012

Biomed Rep. 2026 Apr 24;24(6):74. doi: 10.3892/br.2026.2147. eCollection 2026 Jun.

ABSTRACT

Hepatocellular carcinoma (HCC) shows a marked predominance in men, yet the molecular basis for this sex disparity remains unclear. The present study leveraged multi-omics data and machine learning algorithms to identify key genes associated with sex-specific differences in HCC and to screen for putative candidate compounds, aiming to provide new insights for sex-specific therapy. The mRNA expression data of male and female patients with HCC and paracancerous tissues were obtained from the GEO and TCGA databases. To mitigate overfitting, data were partitioned into independent training and testing sets. Candidate genes were screened by differential expression analysis and weighted gene co-expression network analysis. A total of four complementary algorithms, random forest, support vector machines, generalized linear models and extreme gradient boosting were used to identify key genes with high predictive capability. CYP17A1 and IRX3 were identified as the top differentially expressed core genes associated with HCC in men. Pan-cancer analysis showed that CYP17A1 was lowly expressed in the majority of tumors, but significantly highly expressed in HCC, rectal adenocarcinoma and gastric cancer (P<0.001). Functional cell-based assays showed that knockout of CYP17A1 inhibited the proliferation, migration and invasion ability of HCC cells (P<0.001). Immunohistochemistry showed that CYP17A1 protein expression was significantly increased in HCC tissues from male patients when compared with that in paracancerous tissues (P<0.001), whereas there was no significant difference in female patient tissues (P>0.05). Notably, while IRX3 was identified computationally, its functional role remains to be experimentally validated. Molecular docking predicted a potential interaction between the natural compound Saikosaponin A and the CYP17A1 protein, and cellular assays revealed that it dose-dependently inhibits HCC cell malignant phenotypes. The present study suggests that CYP17A1 is associated with sex differences in HCC, potentially via the androgen signaling axis. Furthermore, IRX3 emerges as a novel hypothesis-generating candidate gene. Finally, the findings of the present study highlight Saikosaponin A as a putative therapeutic candidate for male patients with HCC, warranting further target-dependency investigations.

PMID:42125766 | PMC:PMC13158723 | DOI:10.3892/br.2026.2147

Microorganisms. 2026 Mar 26;14(4):746. doi: 10.3390/microorganisms14040746.

ABSTRACT

Effective oral interventions for alcohol-induced metabolic stress and liver injury remain limited. Pre-absorptive gastrointestinal alcohol handling is gaining interest as a non-pharmacological strategy to reduce hepatic burden. In this study, we developed a formulation-integrated, food-compatible lyophilized recombinant whole-cell catalyst based on Escherichia coli Nissle 1917 engineered to express alcohol dehydrogenase and acetaldehyde dehydrogenase. Rather than focusing exclusively on strain-level genetic modification, the engineered cells were protected by lyophilization combined with a food-grade chitosan-alginate layer-by-layer coating, forming an artificial cell wall designed to enhance survivability during oral delivery. The formulation resisted simulated gastric acid, sodium taurocholate, and ethanol, retained enzymatic activity after storage, and demonstrated formulation stability. In alcohol-exposed mice, oral administration reduced blood ethanol and acetaldehyde levels, improved liver biochemical parameters, attenuated hepatic steatosis, and partially restored oxidative stress indicators. Integrated multi-omics analyses indicated coordinated gut-associated metabolic and inflammatory responses to alcohol and intervention, rather than a single dominant pathway. These findings provide hypothesis-generating evidence; causality remains to be established. Overall, this study demonstrates a proof-of-concept, food-compatible lyophilized recombinant whole-cell catalyst that integrates enzymatic function with formulation stability and gastrointestinal resilience, highlighting an applied, food-compatible microbial framework for exploring alcohol-related metabolic stress.

PMID:42075143 | PMC:PMC13119499 | DOI:10.3390/microorganisms14040746

Comput Biol Chem. 2026 Apr 23;124(Pt 1):109095. doi: 10.1016/j.compbiolchem.2026.109095. Online ahead of print.

ABSTRACT

Immune checkpoint inhibitors like pembrolizumab exhibit variable efficacy in metastatic gastric cancer (GC). This study aimed to identify molecular drivers of pembrolizumab response, explore mechanisms of immune checkpoint inhibitors (ICIs) efficacy, and develop a prognostic signature. Transcriptomic analysis of pembrolizumab-treated GC (TIGER database) identified 165 response-associated differentially expressed genes (DEGs). Functional annotation and single-cell RNA sequencing (scRNA-seq) data from the Gene Expression Omnibus (GEO) revealed that responder-upregulated genes (R-DEGs) were enriched in immune activation pathways and mainly localized to CD8 + T/NK cells. In contrast, non-responder-upregulated genes (D-DEGs) were linked to extracellular matrix (ECM) remodeling and mainly expressed in fibroblasts/endothelial cells. CellChat analysis demonstrated that key DEGs mediate immune-stromal crosstalk via MHC-I and collagen/laminin signaling. A prognostic signature (Lasso-StepCox[forward] Riskscore; LSR: APOD, APOH, BATF2, GJA1, MAGED1, SLC5A1, SLCO2A1, VWF, VCAN) was derived and validated in four independent GC cohorts from the GEO and Cancer Genome Atlas (TCGA) database. Multi-omics analyses showed that LSR-high tumors exhibited aggressive clinicopathological features, increased stromal components, reduced cytotoxic immune infiltration, diminished tumor mutational burden (TMB), and poorer prognosis. Immunohistochemistry (IHC) and spatial transcriptomics in GC showed that stromal VWF/VCAN expression correlates with reduced CD8⁺ T cell granzyme B expression, suggesting T cell dysfunction. High VWF expression in GC predicted poor survival, and a combined VWF/VCAN score showed enhanced prognostic stratification. This study highlights stromal-immune crosstalk as a driver of pembrolizumab resistance and provides a signature as a clinical tool for prognosis and personalized therapy in metastatic GC.

PMID:42068630 | DOI:10.1016/j.compbiolchem.2026.109095

Chem Biol Drug Des. 2026 Apr;107(4):e70297. doi: 10.1111/cbdd.70297.

ABSTRACT

This study identifies fat mass and obesity-associated protein (FTO) as a pivotal link between metabolic predisposition and pathogenesis associated with Staphylococcus aureus in chronic rhinosinusitis (CRS). These findings were established through the application of an integrative multi-omics framework. We demonstrate that S. aureus upregulates FTO, which functions as an m⁶A demethylase to stabilize the Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1). This molecular axis suppresses GSK-3β and promotes β-catenin nuclear translocation, thereby driving epithelial-mesenchymal transition (EMT) and pathological mucosal remodeling. By mapping the FTO-MALAT1-GSK-3β/β-catenin signaling network, this research elucidates how metabolic susceptibility facilitates infection-triggered epithelial reprogramming. These findings establish FTO as a promising biomarker and potential therapeutic target, providing a systemic foundation for personalized CRS treatment strategies.

PMID:41973807 | DOI:10.1111/cbdd.70297