Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer. Although immune checkpoint inhibitors (ICIs) have brought new treatment options for advanced patients, a considerable proportion still shows limited response. Mitochondrial dysfunction plays a crucial role in tumor development and immune evasion, but its regulatory mechanisms in LUAD immune microenvironment remain unclear.
We integrated 149 mitochondria-related pathways (1,136 coding proteins) to develop and validate the Mitochondrial Pathway Signature (MitoPS) using machine learning approaches across seven independent LUAD cohorts (n=1,231). The system was systematically compared with 129 published LUAD prognostic signatures and validated in seven immunotherapy cohorts (n=451). Multiomics analysis, immunofluorescence staining, and experimental validation were performed to investigate its molecular mechanism.
MitoPS demonstrated consistent predictive performance across validation cohorts, with high scores indicating poor prognosis, outperforming 129 existing prognostic models. In immunotherapy cohorts, MitoPS reliably predicted treatment response and prognosis. Immune microenvironment analysis revealed that low MitoPS scores correlated with higher immune cell infiltration and active immune function. Mechanistic studies identified mitochondria-related gene NDUFB10 as a core gene of MitoPS (r=0.38, p<0.05), where its high expression was significantly associated with immune desert phenotype and worse prognosis. Functional experiments confirmed that NDUFB10 knockdown significantly enhanced ICIs therapy and increased GZMB+CD8+T cell infiltration, indicating NDUFB10's crucial role in regulating tumor immune microenvironment and immunotherapy response.
The MitoPS scoring system reliably predicts prognosis and immunotherapy response in patients with LUAD, providing a novel reference for clinical decision-making. Furthermore, its core gene NDUFB10 regulates tumor immune microenvironment, offering a potential therapeutic target for improving immunotherapy outcomes.
© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.

Atopic dermatitis (AD) is a chronic inflammatory skin disorder caused by immune dysregulation that involves the release of various pro-inflammatory cytokines. Patients with AD frequently exhibit basophil infiltration in the affected skin. Although the role of the NLRP3 inflammasome in innate immune cells has been extensively studied, the contribution of the basophil inflammasome to the pathophysiology of AD remains to be elucidated. In this study, we demonstrated that IL-33 primes the NLRP3 inflammasome in basophils, leading to the production and release of mature IL-1β. Mechanistically, we showed that IL-33 stimulation induced pro-IL-1β and NLRP3 expression via the NF-κB and p38 MAPK pathways and that basophils released mature IL-1β through the canonical inflammasome activation pathway, which requires NLRP3, ASC, caspase-1, and gasdermin D (GSDMD). In an oxazolone (OXA)-induced AD mouse model, we found that basophils acted as key initiators of inflammation by producing IL-1β in the lesion, and that basophil depletion, genetic ablation of Nlrp3 or Il1b, or basophil-specific genetic ablation of Nlrp3 ameliorated ear swelling and neutrophil infiltration. Collectively, these findings establish basophils as a significant early source of NLRP3 inflammasome-driven IL-1β, contributing to the pathogenesis of AD. Targeting the IL-33/ST2L axis or NLRP3 inflammasome activation in basophils may offer a promising therapeutic strategy for managing AD.
© 2025. The Author(s).

Cisplatin and oxaliplatin are among the most extensively used anti-cancer drugs in the treatment of various types of cancer. However, the cytotoxicity associated with these drugs in normal and adult stem cells is a major concern.
This study aimed to determine the oxidative stress induced by platinum drugs in murine mesenchymal stem cells (mMSCs).
mMSCs were cultured and treated with cisplatin and oxaliplatin concentrations (5 μM, 15 μM, and 25 μM/L) for 1, 4, 24, 48, and 72 hours. Morphological changes and viability of cells were observed. Oxidative stress was assessed by the expression of 8-Hydroxy-2'-deoxyguanosine (8-OHdG). Necroptosis was determined by Acridine Orange/Ethidium Bromide (AO/EB) staining. Moreover, mRNA levels of DNA repair genes, particularly genes involved in mismatch repair (MMR), including MLH3, MSH2, MLH1, MSH6, and PMS2, and nucleotide excision repair (NER) pathways, such as ERCC1 were measured using Taq-Man Quantitative Real-Time Polymerase Chain Reaction (TaqMan-qRT-PCR).
The proliferation and morphology of mMSCs were noticeably influenced by cisplatin and oxaliplatin at 25 μM, compared to 5 μM and 15 μM by 72 hours. 8OHdG positive and necroptotic cells were significantly (P < 0.001) high from 24 to 72 hours among 25 μM drug-treated mMSCs. The concentration and temporal oxidative stress generated in mMSCs by cisplatin and oxaliplatin disturbed the expression of DNA repair genes at the mRNA level (P < 0.001). Cisplatin remarkably upregulated the expression of MLH1 and PMS2 (≥ 3.0-fold) at 24 hours, while it downregulated MSH2, MLH1, MSH6, and PMS2 (≤ 0.5-fold) at 72 hours. However, oxaliplatin noticeably caused the upregulation of MLH3 and ERCC1 expression (≥ 3.0-fold) at 24-48 hours, and downregulation of MSH2, MLH1, MSH6, PMS2, and ERCC1 (≤ 0.5-fold) at 72 hours.
This suggests that adult stem cells in tissues and organs are highly vulnerable to platinum drugs during cancer treatment. Additional studies on localized treatments may help to prevent adverse effects on normal cells.
AJSC Copyright © 2025.

DNA methylation plays a fundamental role in regulating transcription during development and differentiation. However, its functional role in the regulation of endothelial cell (EC) transcription during state transition, meaning the switch from an angiogenic to a quiescent cell state, has not been systematically studied. Here, we report the longitudinal changes of the DNA methylome over the lifetime of the murine pulmonary vasculature. We identified prominent alterations in hyper- and hypomethylation during the transition from angiogenic to quiescent ECs. Once a quiescent state was established, DNA methylation marks remained stable throughout EC aging. These longitudinal differentially methylated regions correlated with endothelial gene expression and highlighted the recruitment of de novo DNA methyltransferase 3a (DNMT3A), evidenced by its motif enrichment at transcriptional start sites of genes with methylation-dependent expression patterns. Loss-of-function studies in mice revealed that the absence of DNMT3A-dependent DNA methylation led to the loss of active enhancers, resulting in mild transcriptional changes, likely due to loss of active enhancer integrity. These results underline the importance of DNA methylation as a key epigenetic mechanism of EC function during state transition. Furthermore, we show that DNMT3A-dependent DNA methylation appears to be involved in establishing the histone landscape required for accurate transcriptome regulation.
© The Author(s) 2025. Published by Oxford University Press on behalf of Nucleic Acids Research.

The inflammatory response after myocardial infarction (MI) is a precisely regulated process that greatly affects subsequent wound healing and remodeling. However, understanding about the process is still limited. Macrophages are critically involved in inflammation resolution after MI. Krüppel-like factor 9 (Klf9) is a C2H2 zinc finger-containing transcription factor that has been implicated in glucocorticoid regulation of macrophages. However, the contribution of Klf9 to macrophage phenotype and function in the context of MI remains unclear. Our study revealed that KLF9 deficiency resulted in higher mortality and cardiac rupture rate, as well as a considerable exacerbation in cardiac function. Single-cell RNA sequencing and flow cytometry analyses revealed that, compared with WT mice, Klf9-/- mice displayed excessive neutrophil infiltration, insufficient macrophage infiltration, and a reduced proportion of monocyte-derived CD206+ macrophages after MI. Moreover, the expression of IFN-γ/STAT1 pathway genes in Klf9-/- cardiac macrophages was dysregulated, characterized by insufficient expression at 1 day post-MI and excessive expression at day 3 post-MI. Mechanistically, Klf9 directly binds to the promoters of Stat1 gene, regulating its transcription. Overall, these findings indicate that Klf9 beneficially influences wound healing after MI by modulating macrophage recruitment and differentiation by regulating the IFN-γ/STAT1 signaling pathway.