Esophageal squamous cell carcinoma (ESCC) ranks among the primary contributors to cancer‑related mortality in China. Resistance to paclitaxel markedly diminishes its therapeutic effectiveness and outcomes. Anaerobic glycolysis is a pivotal mechanism in cancer progression. Insulin‑like growth factor 2 mRNA binding protein 2 (IGF2BP2) as a reader of RNA N6‑methyladenosine (m6A) modification ensures the stability of RNA at the post‑transcriptional level. Nonetheless, the role and mechanism of IGF2BP2 in mediating paclitaxel resistance and anaerobic glycolysis in ESCC remain unclear. The current study selected two ESCC cell lines (KYSE30 and KYSE150). Cell proliferation and clonogenic ability were assessed via functional experiments. Apoptosis was quantified through flow cytometry. The rate of anaerobic glycolysis was determined via glycolysis assays. The stability of Forkhead box M1 (FOXM1) mRNA was assessed through reverse transcription‑quantitative polymerase chain reaction following actinomycin D treatment. Protein levels were analyzed through western blotting. Bioinformatics analysis revealed an overexpression of IGF2BP2 in ESCC. Furthermore, IGF2BP2 silencing inhibited cell proliferation and clonogenic activity. RNA and m6A‑sequencing results suggested that FOXM1 is critical to IGF2BP2‑mediated paclitaxel resistance in ESCC. Additionally, it was discovered that the silencing of IGF2BP2 compromises FOXM1 mRNA stability, reduces anaerobic glycolysis, and diminishes paclitaxel resistance. Finally, FOXM1 overexpression mitigated the effects of IGF2BP2 silencing in ESCC cells. The current findings underscore the significant role of the IGF2BP2‑FOXM1 signaling pathway in modulating anaerobic glycolysis and paclitaxel resistance in ESCC, offering insights into future therapeutic approaches to this malignancy.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with KRAS mutations in ~ 95% of cases. While KRAS inhibitors have shown promise, therapeutic resistance necessitates combination approaches. In particular, it is important to understand how downstream signaling of KRAS supports PDAC growth. For example, DUSP6 has emerged as an important dual-specificity phosphatase regulating KRAS-MAPK signaling. DUSP6 is markedly overexpressed in PDAC tumors compared to normal pancreatic tissue, with transcriptomic and single-cell RNA-seq analyses revealing its enrichment in epithelial tumor cells, especially in metastatic lesions. High DUSP6 expression correlates with the quasi-mesenchymal/squamous molecular subtype and poorer survival outcomes. Gene set enrichment analyses linked DUSP6 to pathways involved in cell migration and metabolism in metastatic samples. Functionally, DUSP6 knockdown in PDAC cells increases ERK/MAPK activation and alters migration. Metabolic profiling revealed enhanced basal glycolysis upon DUSP6 suppression. However, combined glycolysis inhibition and DUSP6 knockdown did not affect migration, suggesting that glycolytic changes are not the driver of altered migratory behavior. These findings reveal that DUSP6 independently regulates migration and metabolism in PDAC, emphasizing its dual role in disease progression. This study underscores the significance of DUSP6 as a potential therapeutic target and provides new insights into its contributions to PDAC progression.
© 2025. The Author(s).

Different signaling pathways connect the mitochondrion with the transcriptional machinery in the nucleus. Redox events are thought to play a substantial role along this axis, however, many open questions about their specificity and mode of action remain. Here, we have employed subtoxic doses of the complex I inhibitor MPP+ in human neuronal LUHMES cells to characterize the contribution of scavengeable redox signals to mito-nuclear communication. MPP+ evoked a broadly targeted transcriptional induction of nuclear-encoded respiratory chain complex (RCC) subunits. Nanomolar doses of phenothiazine (PHT), a mitochondrially active antioxidant, attenuated these transcriptional effects by approximately half, but did not modulate the bioenergetic markers ATP, NAD+, NADH, lactate, or glucose. Transcriptional induction by MPP+ was accompanied by a loss of nuclear 5-methyl-cytosine and an increase in histone H3K14 acetylation, both of which were entirely prevented by PHT. Inhibitor and PHT reversibility experiments suggested that these alterations were mediated by lowered DNMT3B and SIRT1 levels, respectively. Analysis of MPTP-treated mice recapitulated the PHT-reversible induction of histone acetylation and DNMT3B suppression in vivo. Moreover, PHT completely abrogated the statistical significance of the association of MPP+ with the selective induction of mitochondrially imported proteins and RCC subunits. We conclude that the mitochondrion employs a redox signal to announce impending, but not yet acute mitochondrial distress to the nucleus, in order to selectively upregulate mito-metabolic genes via chromatin reorganization. Our results have implications for the interpretation of the observed epigenetic changes in Parkinson's disease and other neurodegenerative disorders.
Copyright © 2025 Baeken, Borlepawar, Kötzner, Richly, Behl, Moosmann and Hajieva.

In the present study, we aim to identify a potential drug candidate that targets the Monocarboxylate Transporter-4 (MCT-4) protein. Syrosingopine (SRY) is a well-established inhibitor of lactate transport through MCT-4. We screened 2,11,192 potential leads through ZINC database, which were atleast 50 % structurally similar with SYR. After in-depth analysis, 900 molecules were shortlisted based on Lipinski's rule, optimal molecular weight, binding energy, hydrogen bonding, and ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties that render them viable MCT-4 inhibitors. The outcome underscored Brucine (BRU) as the most promising lead molecule within a cohort of ten potential compounds. BRU is a monoterpenoid indole alkaloid and is used in the regulation of high blood pressure and other comparatively benign cardiac ailments. As such, no reports is available emphasizing the efficacy of BRU on lactate transport or mammary gland carcinoma. BRU demonstrated strong affinity for the MCT-4 transporter's catalytic domain, forming significant hydrophobic and polar interactions with essential amino acids at the binding site. BRU demonstrated significant cytotoxicity and increased the extracellular lactate levels in MCF-7 cells. The findings strongly encouraged BRU's effectiveness, offering promising paths for subsequent investigations.
© 2025 The Authors.

Rapid hematopoietic adaptations are important for building and sustaining the biological response to β-glucan. The signals involved in these early events have not yet been fully explored. Given that type I interferons are produced in response to β-glucan and can profoundly impact hematopoietic stem cell (HSC) function, we hypothesized that this pathway may be involved in the early bone marrow response to β-glucan. In vivo administration of β-glucan led to local interferon-α production in the peritoneal cavity and bone marrow, upregulation of its receptor, IFNAR1, specifically on long-term hematopoietic stem cells (LT-HSCs), and broad expansion of downstream progenitor subpopulations. We demonstrate that intact type I interferon signaling is critical for β-glucan-mediated LT-HSC proliferation, mitochondrial activity, and glycolytic commitment. By determining that type I interferon signaling is important for LT-HSCs, which sit at the apex of the hematopoietic hierarchy, we uncover an important component of the early inflammatory response to β-glucan.
© 2025 The Author(s).