Transl Res. 2026 Sep 13:S1931-5244(26)00195-7. doi: 10.1016/j.trsl.2026.09.009. Online ahead of print.

ABSTRACT

Gemcitabine resistance remains a major barrier to effective therapy in pancreatic ductal adenocarcinoma (PDAC), and current combination regimens show potential to overcome this resistance. Here, we identify the mitochondrial ribosomal proteins MRPS22 and MRPL3 as key metabolic gatekeepers that maintain mitochondrial OXPHOS and pyrimidine metabolism, thereby promoting pancreatic cancer cell proliferation and chemoresistance. Across independent cohorts, high MRPS22/MRPL3 expression associates with poorer survival. Depletion of either gene in PDAC curtailed cell proliferation and xenograft growth, which might be due to an impaired mitochondria function, including destabilized respiratory super-complex assembly, diminished ATP production, and increased oxidative stress. Multi-omics profiling revealed a broad reduction of central-carbon intermediates and a pronounced blockade of de novo pyrimidine synthesis at the dihydroorotate dehydrogenase (DHODH) node. MRPS22 depletion hampered nucleotide-pool generation, and exogenous deoxynucleotides partially rescued PDAC cell growth when MRPs were knocked down. Pharmacologic OXPHOS inhibition increased gemcitabine sensitivity, whereas gemcitabine-resistant derivatives exhibited heightened OXPHOS activity and upregulated mitochondrial ribosomal programs. Co-targeting OXPHOS (antimycin A) or DHODH (brequinar) with gemcitabine produced Loewe synergy in vitro and suppressed growth of gemcitabine-resistant xenografts without affecting body weight. Collectively, these findings established MRPS22/MRPL3 as translation-level drivers of PDAC metabolic fitness and nominate OXPHOS/DHODH blockade as a rational combination strategy to overcome gemcitabine resistance.

PMID:42732873 | DOI:10.1016/j.trsl.2026.09.009

Front Immunol. 2026 Aug 18;17:1904638. doi: 10.3389/fimmu.2026.1904638. eCollection 2026.

ABSTRACT

BACKGROUND: Aberrant tissue repair and relentless fibroblast activation are hallmark features of idiopathic pulmonary fibrosis (IPF). Although IPF and Alzheimer's disease (AD) share underlying aging-related pathologies, including immune and metabolic dysregulation, the putative genetic mechanisms linking AD susceptibility to pathogenic macrophage remodeling in the fibrotic niche are not fully established.

METHODS: We performed a two-sample Mendelian randomization (MR) analysis to assess the genetic association and potential causal relationship between AD and IPF. Shared hub genes were identified via protein interaction networks. To characterize macrophage heterogeneity and intercellular crosstalk within the IPF microenvironment, we interrogated scRNA-seq data (GSE122960) utilizing Monocle 3 and CellChat algorithms. The functional essentiality of APOE was evaluated bridging computational virtual knockout (scTenifoldKnk) with laboratory in vitro assays. Specifically, downstream transcriptomic shifts and fibroblast activation capacities were validated using APOE-silenced THP-1 macrophages and a Transwell co-culture model with MRC-5 cells.

RESULTS: MR estimates indicated that genetic liability to AD is associated with a lower risk of developing IPF. Integrated profiling identified the lipid-metabolism gene APOE as a central hub, specifically enriched in lung macrophages. Pseudotime modeling captured a pathogenic bifurcation in IPF, where macrophages evolve toward a terminal state marked by profound oxidative phosphorylation defects and massive SPP1 secretion. These SPP1+ macrophages primarily activate fibroblasts via CD44 and integrin signaling axes. Furthermore, both virtual simulations and in vitro THP-1 experiments demonstrated that loss of APOE function triggers the hyperactivation of complement (C1QA) and antigen-presentation (HLA-DR) pathways. Co-culture assays ultimately confirmed that APOE ablation in macrophages strongly exacerbates myofibroblast differentiation (elevated α-SMA and collagen I) in adjacent MRC-5 cells.

CONCLUSION: APOE functions as a vital metabolic barrier against pro-fibrotic macrophage polarization in the lung. Disruption of this specific lipid metabolic network is strongly associated with SPP1-driven fibroblast activation and local immune imbalance, providing a theoretical framework that strictly warrants future in vivo investigation to determine its clinical relevance.

PMID:42682427 | PMC:PMC13529525 | DOI:10.3389/fimmu.2026.1904638

J Hazard Mater. 2026 Sep 15;516:143449. doi: 10.1016/j.jhazmat.2026.143449. Epub 2026 Aug 30.

ABSTRACT

The global incidence of ulcerative colitis (UC) has significantly increased in rapidly industrializing nations, with numerous studies highlighting environmental exposures, particularly nitrogen dioxide (NO₂), as potential contributors to disease susceptibility. However, the clinical implications and molecular mechanisms linking NO₂ exposure to UC susceptibility remain poorly understood. This study investigated the associations between NO₂ and UC by integrating multi-omics data. We identified a CD8⁺ T cell subpopulation with a distinct phenotype characterized by perforin production, which potentially exacerbated colonic inflammation related to NO₂ exposure. To validate this hypothesis, we established mouse models exposed to NO₂, confirming increased CD8⁺ T cell infiltration and elevated perforin secretion through immunofluorescent (IF) staining. Employing artificial intelligence techniques, we identified Cell Division Cycle 25B (CDC25B) as a gene of interest correlated with putative NO₂-related UC signatures. Finally, through molecular docking (MD) and molecular dynamics simulations (MDS), we identified ozanimod as one of several computationally nominated compounds associated with the CDC25B‑related network; however, none of these computational predictions were experimentally validated in the present study. Collectively, these findings suggest a correlative link between perforin or CD8⁺ T cell-associated colonic inflammation and NO₂-associated UC susceptibility, and nominate CDC25B as a candidate gene for further investigation.

PMID:42679583 | DOI:10.1016/j.jhazmat.2026.143449

Mol Divers. 2026 Apr 12. doi: 10.1007/s11030-026-11545-y. Online ahead of print.

NO ABSTRACT

PMID:41966666 | DOI:10.1007/s11030-026-11545-y