Phytomedicine. 2026 Aug 26;161:158760. doi: 10.1016/j.phymed.2026.158760. Online ahead of print.

ABSTRACT

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) harbors TP53 mutations at high frequency, yet therapeutic strategies that specifically target mutant p53 remain limited.

PURPOSE: This study aimed to identify S100A6, a calcium-binding protein frequently upregulated in TP53-mutant PDAC, as a critical regulator of mutant p53 stability and tumor progression, and to explore potential S100A6-targeting agents for therapeutic intervention.

METHODS: We integrated computer-assisted drug screening with transcriptomics, acetylation omics, and molecular biology techniques to identify Agrimol B (AgrB), a bioactive compound derived from the traditional Chinese herb Agrimonia pilosa Ledeb., as a potential S100A6-targeting agent.

RESULTS: High S100A6 expression was closely associated with poor prognosis in patients with TP53-mutant PDAC, whereas S100A6 depletion markedly suppressed PDAC cell growth and metastatic potential. Mechanistically, AgrB enhanced the interaction between S100A6 and the deacetylase HDAC2, leading to reduced acetylation of mutant p53 at lysine 382. This disruption activated autophagy-dependent cell death and thereby inhibited PDAC progression.

CONCLUSION: Our findings reveal an S100A6-HDAC2-mutant p53 acetylation axis that regulates TP53-mutant pancreatic tumorigenesis, providing mechanistic evidence supporting S100A6 as a therapeutic vulnerability and highlighting AgrB as a promising natural-product-derived candidate for further development against this aggressive malignancy.

PMID:42700714 | DOI:10.1016/j.phymed.2026.158760

bioRxiv [Preprint]. 2026 May 5:2026.04.30.721768. doi: 10.64898/2026.04.30.721768.

ABSTRACT

In biomedical scientific discovery, synthesizing prior knowledge from the literature is an essential component of interpreting numerical omics data analyses for disease target identification and drug discovery. Large language models (LLMs) alone can rapidly retrieve disease mechanisms from biomedical text, but text-only outputs are general and unreliable for target and drug prioritization without cohort-specific quantitative evidence. Herein, we propose a provenance-aware Text-to-Target framework that couples schema-constrained multi-model LLM retrieval with numeric omics data analysis. The key design is a modality-aware fusion step: candidates are partitioned into overlap-supported anchors, retrieval-only hidden hubs, and network-emergent novelty nodes, then propagated into staged hypothesis and strategy generation under topology constraints. We evaluate the model in Alzheimer's disease (AD) and pancreatic ductal adenocarcinoma (PDAC). In PDAC, the workflow produced a balanced 75-gene candidate universe and a 23-strategy portfolio, with significant DepMap support at both target level and strategy level. In AD, stricter candidate controls yielded a compact 34-gene universe and 14 strategies; under an expanded CRISPRbrain registry, both target-level axes were significant, with strong strategy-level enrichment. Across both diseases, final strategies preserved full provenance closure to the candidate pool, enabling end-to-end auditability from retrieval artifacts to validation outputs. These results support a transferable discovery architecture in which omics evidence constrains biological activity, LLM retrieval expands mechanistic search space, and network-aware fusion preserves interpretability. The framework provides a reproducible basis for dual-disease target prioritization and motivates continuous literature-mechanism concordance with agentic evidence-refresh loops.

PMID:42146439 | PMC:PMC13174328 | DOI:10.64898/2026.04.30.721768

Cancer Discov. 2026 Apr 15. doi: 10.1158/2159-8290.CD-25-1663. Online ahead of print.

ABSTRACT

Brain metastases (BM) remain a devastating disease with dismal prognosis. How circulating tumor cells (CTCs) penetrate the blood brain barrier (BBB) and reprogram the brain microenvironment remain unclear. Using spatially resolved multi-omic profiling of CTCs and brain metastases, integrated with experimental and clinical analyses, we identified Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB) as a CTC-secreted driver of vascular disruption and brain colonization. CBX3 upregulation induced GPNMB expression, which bound endothelial EGFR, triggering CBL-mediated ubiquitination and degradation. Attenuated EGFR signaling suppressed FTO and disrupted endothelial junctions via YTHDF2-dependent TJP1 m6A methylation. Remarkably, GPNMB-induced BBB remodeling promoted immune infiltration via CXCL12-CXCR4 axis, and induced time course-dependent T cell exhaustion within the brain microenvironment. Clinically, elevated CBX3⁺GPNMB⁺ CTCs and plasma CXCL12 were significantly associated with BM progression in lung cancer and melanoma. Therapeutically, dual blockade of GPNMB and PD1 enhanced anti-BM efficacy in mice, unveiling GPNMB as a promising target for precision immunotherapy.

PMID:41973996 | DOI:10.1158/2159-8290.CD-25-1663

Environ Int. 2026 Mar 28;210:110212. doi: 10.1016/j.envint.2026.110212. Online ahead of print.

ABSTRACT

Microplastics (MPs) and nanoplastics (NPs) are pervasive environmental contaminants, raising concerns about their potential to cause inflammation, oxidative stress, and lung injury through respiratory toxicity. Due to their smaller size, larger surface area, and greater reactivity, NPs may pose a greater risk than MPs, yet size-dependent toxicity mechanisms remain unclear. This study investigates the distinct early molecular initiating events and toxicological effects of 1 μm polystyrene MPs (PS-MPs) and 20 nm polystyrene NPs (PS-NPs). Based on the internal exposure dose estimated from Py-GC/MS analysis, in vitro exposure concentrations were set at 0, 62.5, 125, 250, 500, and 1000 μg/mL. Multi-omics sequencing and integrative analysis identify specific proteomic and metabolomic alterations. Molecular dynamics simulations and co-immunoprecipitation assays elucidate binding interactions between PS-NPs-induced proteins and metabolic enzymes. In vitro and in vivo experiments reveal a greater accumulation of PS-NPs through endocytosis compared to PS-MPs; while pronounced histopathological damage with inflammatory response in mice lungs were only induced by PS-NPs, rather than PS-MPs. Compared to control group, PS-MPs partly caused proteomic or metabolomic perturbations, while PS-NPs induced significant differential expression of more extensive proteins and metabolites. PS-NPs exposure specifically upregulates insulin-like growth factor 2 receptor (IGF2R) expression and reduces Hypoxanthine levels when compared with PS-MPs. IGF2R directly interacts with Hypoxanthine-guanine phosphoribosyl transferase (HPRT), a key enzyme in Hypoxanthine metabolism, causing its disruption. This study provides important insights into the comparative toxic effects between PS-NPs with PS-MPs, especially the unique toxicological mechanisms of PS-NPs, thereby advancing the understanding of airborne plastic pollutant risks and supporting future regulatory assessments.

PMID:41921402 | DOI:10.1016/j.envint.2026.110212

Front Immunol. 2026 Mar 13;17:1770348. doi: 10.3389/fimmu.2026.1770348. eCollection 2026.

ABSTRACT

Interstitial lung disease (ILD) is one of the most common extra-articular manifestations of rheumatoid arthritis (RA). Some patients with RA-ILD may develop progressive pulmonary fibrosis, leading to severe impairment of lung function and respiratory failure, which impacts quality of life and can even be life-threatening. This review identified genetic susceptibility, environmental factors, and immune dysregulation as key contributors to the etiology and pathogenesis of RA-ILD. We highlight that autoantibodies, adaptive immune abnormalities, and tertiary lymphoid organ formation significantly drive pulmonary inflammation and fibrosis, while pro-inflammatory cytokines and epithelial-mesenchymal transition (EMT) further contribute to lung tissue injury. Current treatment options, including glucocorticoids, immunosuppressants, and antifibrotic agents such as nintedanib and pirfenidone, are often limited by substantial side effects. Additionally, emerging therapies like JAK inhibitors, CAR-T cells, and the upcoming phosphodiesterase-4B inhibitor, nerandomilast, show promise, but no curative treatment exists to date. Future research could focus on multi-omics technologies and conducting multicenter clinical trials to establish therapeutic targets and advance precision medicine for RA-ILD.

PMID:41909710 | PMC:PMC13021622 | DOI:10.3389/fimmu.2026.1770348