Cell. 2026 Sep 29:S0092-8674(26)01081-0. doi: 10.1016/j.cell.2026.09.012. Online ahead of print.

ABSTRACT

Cachexia is a major cause of morbidity in pancreatic cancer, but the cellular circuitry linking tumor progression to systemic wasting remains incompletely understood. Integrating single-cell RNA sequencing, Xenium spatial transcriptomics, multiplex immunohistochemistry, bulk transcriptomics, and functional studies across human non-cachexia, pre-cachexia, and cachexia samples, together with mouse models, we define a cachexia-associated microenvironmental niche composed of SEMA4A⁺ tumor cells, AQP9⁺ macrophages, and LOXL2⁺ cancer-associated fibroblasts. Mechanistically, SEMA4A-associated signaling promotes bone morphogenetic protein-2 (BMP2)-dependent acquisition of an AQP9-associated macrophage phenotype, and macrophage-derived CXCL8 activates LOXL2⁺ fibroblasts. LOXL2⁺ fibroblasts reciprocally enhance tumor cell FOSL1/SEMA4A signaling through exosomal N-glycosylated LOXL2. Spatial analyses demonstrate progressive enrichment of this niche with cachexia severity and association with postoperative development of cachexia in previously non-cachectic patients. These findings provide a framework linking local tumor ecosystem dynamics to cachexia progression.

PMID:42810340 | DOI:10.1016/j.cell.2026.09.012

Nat Commun. 2026 Aug 29;17(1):10311. doi: 10.1038/s41467-026-77187-8.

ABSTRACT

Type 2 diabetes (T2D) subgroups defined by clinical variables differ in disease progression and treatment response. To uncover potential molecular drivers of this heterogeneity, we performed a multi-omics analysis of 826 drug-naïve T2D patients from two phase 3 trials of the insulin sensitizer chiglitazar. Here we show that severe insulin-resistant diabetes (SIRD) is characterized by distinct miRNA profiles (e.g., miR-122-5p) correlated with liver injury, and metabolic shifts in amino acids and primary bile acids. Mild obesity-related diabetes (MOD) showed the lowest level of phenylacetylglutamine, a metabolite known to promote cardiovascular disease. Severe insulin-deficient diabetes (SIDD) exhibited high pancreas-specific miR-7-5p, while mild age-related diabetes (MARD) presented the mildest abnormalities. Finally, integrating these multi-omics signatures into machine learning models enhanced prediction of insulin sensitizer efficacy over clinical data alone. Our findings define the distinct molecular signatures of T2D subgroups, facilitating the prediction of heterogeneous treatment responses and supporting personalized clinical management.

PMID:42805981 | PMC:PMC13620142 | DOI:10.1038/s41467-026-77187-8

Drug Des Devel Ther. 2026 Sep 5;20:543657. doi: 10.2147/DDDT.S543657. eCollection 2026.

ABSTRACT

Metabolic dysfunction-associated steatohepatitis (MASH) is not solely a disorder of hepatocellular lipid accumulation, but a multicellular disease driven by coordinated metabolic stress, sterile inflammation, fibrogenesis, and niche remodeling. Recent therapeutic progress with the provisional approval of resmetirom and semaglutide has validated MASH as a tractable clinical target. However, many experimental agents have shown limited or inconsistent efficacy, particularly for regression of hepatic fibrosis or cirrhosis, reflecting the biological heterogeneity and dynamic cellular architecture of the disease. Distinct from conventional pathway- or drug class-based reviews, we summarize emerging therapeutics through a liver cell-centered framework, integrating hepatocyte-directed metabolic therapies, immune-cell modulation, hepatic stellate cell-targeted antifibrotic strategies, niche-directed approaches involving liver sinusoidal endothelial cells and cholangiocytes, systemic multi-cell modulators, and precision-delivery technologies. We further compare how these interventions reshape pathogenic communication among hepatic and extrahepatic compartments, while emphasizing unresolved challenges in drug target selection, cellular specificity, disease-stage dependency, safety, and patient stratification. This perspective emphasizes the need to move from isolated pathway targeting toward cell- and network-informed therapeutic strategies supported by spatial multi-omics, human-relevant models, and precision delivery.

PMID:42719321 | PMC:PMC13557022 | DOI:10.2147/DDDT.S543657

Chin J Cancer Res. 2026 Aug 30;38(4):480-500. doi: 10.21147/j.issn.1000-9604.2026.04.08.

ABSTRACT

OBJECTIVE: Breast cancer remains a leading cause of global cancer mortality, characterized by profound heterogeneity. While immune checkpoint blockade (ICB) has transformed oncology, its efficacy in breast cancer is often hindered by "immune-cold" microenvironments and immune exclusion. Programmed cell death (PCD) is a critical regulator of tumor immune microenvironment (TIME). However, its role in the breast cancer immune microenvironment remains poorly understood.

METHODS: We integrated multi-omics data from six breast cancer cohorts (N=3,764) to develop a programmed cell death learning signature (PCDsig) using over 100 machine learning combinations. The model was benchmarked against 29 published signatures. Single-cell transcriptomic analysis decoded the immune landscape and cellular crosstalk. The role of adaptor-related protein complex 1 subunit sigma 1 (AP1S1) was validated through a clinical cohort, in vitro functional assays, and in vivo syngeneic mouse models.

RESULTS: PCDsig significantly stratified patient prognosis across all cohorts, consistently outperforming 29 existing models. High PCDsig scores correlated with immune-excluded phenotypes, reduced CD8+ T cell infiltration, and lower immunophenoscores. Single-cell analysis revealed that high-PCDsig tumors utilize vascular endothelial growth factor A (VEGFA) signaling to foster an immunosuppressive microenvironment. AP1S1 was identified as the core driver of immune exclusion. And our clinical cohort supported the immune exclusion effect of AP1S1. AP1S1 knockdown impaired tumor progression in vitro and fundamentally remodeled the tumor immune ecosystem in vivo. Combining AP1S1 inhibition with anti-programmed cell death ligand 1 (anti-PD-L1) therapy exerted profound synergistic effects, driven by massive infiltration and functional activation of cytotoxic Granzyme B (GZMB)+CD8+ T cells.

CONCLUSIONS: Our study establishes the PCDsig we developed is a potential prognostic and predictive biomarker for breast cancer. We provide the first evidence of AP1S1 as a core immunomodulatory oncogene that mediates immune exclusion. Targeting AP1S1 represents a highly promising strategy to sensitize cold breast tumors to ICB, offering a new perspective for precision immunotherapy.

PMID:42712842 | PMC:PMC13551362 | DOI:10.21147/j.issn.1000-9604.2026.04.08

Free Radic Biol Med. 2026 Sep 9;256:441-460. doi: 10.1016/j.freeradbiomed.2026.09.006. Online ahead of print.

ABSTRACT

Gestational diabetes mellitus (GDM) is a common pregnancy complication with a rising global prevalence, posing serious short-term and long-term health threats to both mothers and offspring. This review repositions GDM as a systemic disorder in which oxidative stress acts as a proposed mechanistic hub, linking upstream risk factors to downstream pathophysiology. We first examine how "upstream" factors-including genetic susceptibility, pre-conception status, and environmental exposures-converge to promote a state of pathological redox imbalance. We then examine key mechanistic pathways through which oxidative stress is thought to contribute to systemic insulin resistance and pancreatic β-cell failure, highlighting novel pathways involving intercellular communication via tunneling nanotubes and exosomes. Furthermore, we explore the downstream cascade, where oxidative stress may program maternal accelerated biological aging and multi-organ offspring disease trajectories through nuclear epigenetic programming and mitochondrial dysfunction programming, leaving what has been termed a persistent "metabolic memory". Consequently, this review evaluates emerging strategies that target oxidative stress for early prediction and precision intervention. Early prediction models based on direct redox biomarkers and multi-omics signatures hold potential to shift diagnosis from late-gestation oral glucose tolerance test (OGTT) to first-trimester risk stratification. Current supporting evidence draws from human epidemiological associations, ex vivo placental analyses, and experimental models. However, direct causal and interventional validation in pregnant women remains limited. Integrating targeted redox risk stratification and precision interventions into a life-course clinical framework may help interrupt the intergenerational transmission of metabolic disease initiated by GDM.

PMID:42716407 | DOI:10.1016/j.freeradbiomed.2026.09.006

Chin J Cancer Res. 2026 Aug 30;38(4):480-500. doi: 10.21147/j.issn.1000-9604.2026.04.08.

ABSTRACT

OBJECTIVE: Breast cancer remains a leading cause of global cancer mortality, characterized by profound heterogeneity. While immune checkpoint blockade (ICB) has transformed oncology, its efficacy in breast cancer is often hindered by "immune-cold" microenvironments and immune exclusion. Programmed cell death (PCD) is a critical regulator of tumor immune microenvironment (TIME). However, its role in the breast cancer immune microenvironment remains poorly understood.

METHODS: We integrated multi-omics data from six breast cancer cohorts (N=3,764) to develop a programmed cell death learning signature (PCDsig) using over 100 machine learning combinations. The model was benchmarked against 29 published signatures. Single-cell transcriptomic analysis decoded the immune landscape and cellular crosstalk. The role of adaptor-related protein complex 1 subunit sigma 1 (AP1S1) was validated through a clinical cohort, in vitro functional assays, and in vivo syngeneic mouse models.

RESULTS: PCDsig significantly stratified patient prognosis across all cohorts, consistently outperforming 29 existing models. High PCDsig scores correlated with immune-excluded phenotypes, reduced CD8+ T cell infiltration, and lower immunophenoscores. Single-cell analysis revealed that high-PCDsig tumors utilize vascular endothelial growth factor A (VEGFA) signaling to foster an immunosuppressive microenvironment. AP1S1 was identified as the core driver of immune exclusion. And our clinical cohort supported the immune exclusion effect of AP1S1. AP1S1 knockdown impaired tumor progression in vitro and fundamentally remodeled the tumor immune ecosystem in vivo. Combining AP1S1 inhibition with anti-programmed cell death ligand 1 (anti-PD-L1) therapy exerted profound synergistic effects, driven by massive infiltration and functional activation of cytotoxic Granzyme B (GZMB)+CD8+ T cells.

CONCLUSIONS: Our study establishes the PCDsig we developed is a potential prognostic and predictive biomarker for breast cancer. We provide the first evidence of AP1S1 as a core immunomodulatory oncogene that mediates immune exclusion. Targeting AP1S1 represents a highly promising strategy to sensitize cold breast tumors to ICB, offering a new perspective for precision immunotherapy.

PMID:42712842 | PMC:PMC13551362 | DOI:10.21147/j.issn.1000-9604.2026.04.08

J Ethnopharmacol. 2026 Sep 5;374(Pt 1):122370. doi: 10.1016/j.jep.2026.122370. Online ahead of print.

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Wuwei Huanglian Wan (WWHLW) is a traditional Tibetan medicine formula developed by Tibetan physician Takpe Pingcuo and officially documented in the Ministry of Health Drug Standards for Tibetan Medicines (Volume I, 1995). It has long been used for the treatment of gastrointestinal disorders, particularly conditions associated with gastrointestinal discomfort and inflammation. Given the overlap between its traditional indications and the clinical manifestations of H. pylori-associated gastritis (HAG), WWHLW represents a promising candidate for the management of H. pylori infection and related gastric inflammation. In addition, several constituent herbs of WWHLW have demonstrated anti-H. pylori and anti-inflammatory activities, providing a pharmacological basis for further investigating its therapeutic effects.

AIM OF THE STUDY: This study aimed to systematically evaluate the therapeutic effects of WWHLW against H. pylori infection and HAG, and to explore the biological processes associated with these effects through integrated multi-omics and experimental validation.

MATERIALS AND METHODS: The therapeutic effects of WWHLW were evaluated through in vitro antibacterial assays and an H. pylori-infected mouse model. UHPLC-HRMS/MS was employed for chemical profiling and identification of serum-absorbed constituents. Serum metabolomics, 16S rRNA gene sequencing, network pharmacology analysis, molecular docking analysis, and molecular biological analyses were integrated to investigate the metabolic, microbial, and signaling changes associated with its therapeutic activity.

RESULTS: WWHLW exhibited anti-H. pylori activity, with minimum inhibitory concentrations (MICs) of 0.2-0.5 mg/mL against both standard strains and multidrug-resistant clinical isolates. At MIC concentrations, WWHLW treatment altered the expression of multiple virulence-associated genes and reduced gastric H. pylori colonization by 93.8% in infected mice. UHPLC-HRMS/MS analysis putatively annotated 121 compounds in the WWHLW extracts, of which 10 prototype constituents were detected in serum after oral administration. Integrated metabolomics and network pharmacology analyses revealed alterations in lipid and amino acid-related metabolic pathways following WWHLW treatment. Gut microbiota analysis showed that WWHLW was associated with less pronounced alterations in microbial diversity and composition than antibiotic treatment. Correlation analysis further revealed statistical associations between microbial taxa and lipid and amino acid-related features. Experimental validation showed that WWHLW reduced inflammatory cytokine expression and suppressed STAT3 phosphorylation, consistent with altered IL-6/STAT3-related molecular changes.

CONCLUSIONS: WWHLW exhibits therapeutic potential against H. pylori infection and HAG through combined antibacterial, anti-inflammatory and metabolic regulatory effects. The protective activity of WWHLW was associated with reduced IL-6/STAT3 signaling, providing pharmacological evidence supporting its traditional use in gastrointestinal disorders.

PMID:42700849 | DOI:10.1016/j.jep.2026.122370

Anal Cell Pathol (Amst). 2026;2026(1):e1554526. doi: 10.1155/ancp/1554526.

ABSTRACT

Long noncoding RNAs (lncRNAs) are emerging as critical regulators of tumor initiation and progression through transcriptional and posttranscriptional mechanisms. UPK1A antisense RNA 1 (UPK1A-AS1), a cancer-associated lncRNA, has been reported to participate in oncogenic processes; however, its overall landscape across human malignancies and its biological role in therapy resistance remain poorly understood. Given the increasing importance of identifying functional lncRNAs with prognostic and therapeutic potential, this study presents a comprehensive multiomics characterization of UPK1A-AS1 and its experimental validation in hepatocellular carcinoma (HCC). We integrated datasets from The Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression Project (GTEx), the cancer immunology data engine (CIDE), and the cBioPortal for cancer genomics (cBioPortal) to systematically assess its expression pattern, genomic alterations, clinical significance, and immunological associations. Our analyses revealed that UPK1A-AS1 is significantly upregulated in multiple tumor types, with copy-number amplification as the predominant genomic alteration driving its overexpression. Elevated UPK1A-AS1 expression was correlated with advanced disease stage, poor differentiation, immune exclusion, and unfavorable prognosis, supporting its potential as a cancer type-dependent biomarker. In parallel, functional studies demonstrated that hypoxia transcriptionally induces UPK1A-AS1 in HCC, where it promotes sorafenib resistance by suppressing apoptosis. Silencing UPK1A-AS1 restored apoptotic and enhanced sorafenib efficacy both in vitro and in vivo. Collectively, our findings suggest that UPK1A-AS1 is a hypoxia-inducible oncogenic lncRNA that plays dual roles in cancer, with cancer type-dependent associations with progression and immune modulation across malignancies and mechanistically mediating hypoxia-associated drug resistance in HCC.

PMID:42678131 | PMC:PMC13532061 | DOI:10.1155/ancp/1554526

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

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 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