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Cervical cancer (CC) remains a major health challenge with high mortality rates due to chemoresistance and immune escape. However, the underlying mechanisms remain unclear. We investigated the role of TAB2 in CC using cisplatin‐resistant and parental cell lines. Cell proliferation, migration, sphere formation and T cell‐mediated killing assays were performed. Western blot and qRT‐PCR analysed protein and mRNA expression. NF‐κB pathway involvement was examined using the BAY 11–7082 inhibitor. TAB2 expression was significantly elevated in cisplatin‐resistant CC cells. TAB2 overexpression promoted chemoresistance and immune escape through NF‐κB pathway activation. Conversely, TAB2 knockdown or NF‐κB inhibition sensitised resistant cells to cisplatin and enhanced T cell‐mediated killing. The resistant phenotype could be rescued by restoring PD‐L1 expression. Our findings reveal TAB2 as a critical regulator of both chemoresistance and immune escape in CC through NF‐κB pathway activation. This suggests TAB2 as a potential therapeutic target for overcoming treatment resistance in CC.

Tracheal replacement is a promising approach for treating tracheal defects that are caused by conditions such as stenosis, trauma, or tumors. However, slow postoperative epithelial regeneration often leads to complications, such as infection and granulation tissue formation. Ferroptosis, which is an iron-dependent form of regulated cell death, limits the proliferation of tracheal basal cells (TBCs), which are essential for the epithelialization of tissue-engineered tracheas (TETs). This study explored the potential of ferrostatin-1 (FER-1), which is a ferroptosis inhibitor, to increase TBC proliferation and accelerate the epithelialization of 3D-printed TETs. TBCs were isolated from rabbit bronchial mucosal tissues and cultured in vitro. Ferroptosis was induced in TBCs at passage 2, as shown by increased reactive oxygen species (ROS) levels, Fe 2 ⁺ accumulation, decreased ATP contents, and mitochondrial damage. TBCs were treated with FER-1 (1 μM) for 48 h to inhibit ferroptosis. The effects on ROS levels, Fe 2 ⁺ levels, ATP contents, and mitochondrial morphology were measured. For in vivo experiments, FER-1-treated TBCs were seeded onto 3D-printed polycaprolactone (PCL) scaffolds, which were implanted into rabbits with tracheal injury. Epithelial regeneration and granulation tissue formation were evaluated 6 months after surgery. FER-1 treatment significantly reduced ferroptosis marker levels in vitro; that is, FER-1 treatment decreased ROS and Fe 2 ⁺ accumulation, ameliorated mitochondrial structures, and increased ATP levels. TBC proliferation and viability were increased after ferroptosis inhibition. In vivo, the group that received 3D-printed scaffolds seeded with TBCs exhibited accelerated TET epithelialization and reduced granulation tissue formation compared with the control groups. These results suggest that inhibiting ferroptosis with FER-1 improves TBC function, leading to more efficient tracheal repair. Ferrostatin-1 effectively inhibits ferroptosis in tracheal basal cells, promoting their viability and proliferation. This results in faster epithelialization of tissue-engineered tracheas, offering a promising strategy for improving tracheal reconstruction outcomes and reducing complications such as infection and granulation tissue formation. Future studies are needed to further investigate the molecular mechanisms underlying ferroptosis in TBCs and its potential clinical applications. The online version contains supplementary material available at 10.1186/s13287-025-04263-z.

Red blood cell development from erythroid progenitors requires profound reshaping of metabolism and gene expression. How these transcriptional and metabolic alterations are coupled is unclear. Nprl3 (an inhibitor of mTORC1) has remained in synteny with the α-globin genes for >500 million years, and harbours most of the a-globin enhancers. However, whether Nprl3 serves an erythroid role is unknown. We found that while haematopoietic progenitors require basal Nprl3 expression, erythroid Nprl3 expression is further boosted by the α-globin enhancers. This lineage-specific upregulation is required for sufficient erythropoiesis. Loss of Nprl3 affects erythroblast metabolism via elevating mTORC1 signalling, suppressing autophagy and disrupting glycolysis. Broadly consistent with these murine findings, human NPRL3-knockout erythroid progenitors produce fewer enucleated cells and demonstrate dysregulated mTORC1 signalling in response to nutrient availability and erythropoietin. Therefore, we propose that the anciently conserved linkage of NprI3, α-globin and their associated enhancers has coupled metabolic and developmental control of erythropoiesis. Subject terms: Differentiation, Genomics, Erythropoiesis

Brain organoids have been proposed as suitable human brain model candidates for a variety of applications. However, the lack of appropriate maturation limits the transferability of such functional tools. Here, we present a method to facilitate neuronal maturation by integrating astrocyte-secreted factors into hPSC-derived 2D and 3D neural culture systems. We demonstrate that protein- and nutrient-enriched astrocyte-conditioned medium (ACM) accelerates neuronal differentiation with enlarged neuronal layer and the overproduction of deep-layer cortical neurons. We captured the elevated changes in the functional activity of neuronal networks within ACM-treated organoids using comprehensive electrophysiological recordings. Furthermore, astrocyte-secreted cues can induce lipid droplet accumulation in neural cultures, offering protective effects in neural differentiation to withstand cellular stress. Together, these data indicate the potential of astrocyte secretions to promote neural maturation. Subject terms: Neurological models, Neuronal development

The airway epithelium represents a central barrier against pathogens and toxins while playing a crucial role in modulating the immune response within the upper respiratory tract. Understanding these mechanisms is particularly relevant for red foxes ( Vulpes vulpes ), which serve as reservoirs for various zoonotic pathogens like rabies or the fox tapeworm ( Echinococcus multilocularis ). The study aimed to develop, establish, and validate an air-liquid interface (ALI) organoid model of the fox respiratory tract using primary airway epithelial cells isolated from the tracheas and main bronchi of hunted red foxes. The resulting ALI cultures exhibited a structurally differentiated, pseudostratified epithelium, characterised by ciliated cells, mucus secretion, and tight junctions, as confirmed through histological and immunohistochemical analysis. Functional assessments using a paracellular permeability assay and measurement of transepithelial electrical resistance, demonstrated a tight epithelial barrier. The potential of model’s utility for studying innate immune responses to respiratory infections was validated by exposing the cultures to lipopolysaccharide, phorbol-12-myristate-13-acetate and ionomycin, and nematode somatic antigens. Quantitative PCR revealed notable changes in the expression of pro-inflammatory cytokines TNF and IL-33. This in vitro model represents a significant advancement in respiratory research for non-classical species that may act as important wildlife reservoirs for a range of zoonotic pathogens.

Overall survival of acute myeloid leukemia (AML) remains limited. Inhibitors of the master mitotic kinase PLK1 have emerged as promising therapeutics, demonstrating efficacy in an undefined subset of patients with AML. However, the clinical success of PLK1 inhibitors remains hindered by a lack of predictive biomarkers. The Fanconi anemia (FA) pathway, a tumor-suppressive network comprised of at least 22 genes, is frequently mutated in sporadic AML. In this study, we demonstrate that FA pathway disruption sensitizes AML cells to PLK1 inhibition. Mechanistically, we identify novel interactions between PLK1 and both FANCA and FANCD2 at mitotic centromeres. We demonstrate that PLK1 inhibition impairs recruitment of FANCD2 to mitotic centromeres, induces damage to mitotic chromosomes, and triggers mitotic collapse in FANCA-deficient cells. Our findings indicate that PLK1 inhibition targets mitotic vulnerabilities specific to FA pathway–deficient cells and implicate FA pathway mutations as potential biomarkers for the identification of patients likely to benefit from PLK1 inhibitors. This work demonstrates that FA pathway mutations, which are frequently observed in sporadic AML, induce hypersensitivity to PLK1 inhibition, providing rationale for a novel synthetic lethal therapeutic strategy for this patient population.

Multiple sclerosis (MS) is a chronic inflammatory disease characterized by immune‐mediated demyelination of the central nervous system, resulting in extensive neurological deficit and remyelination impairment. We have previously found that interleukin‐four induced one (IL4I1) protein modulates CNS inflammation and enhances remyelination in mouse models of experimental demyelination. However, it remained unclear if IL4I1 regulates lymphocyte activity in MS. To assess the therapeutic potential of IL4I1 in MS, we investigated the impact of IL4I1 treatment on human lymphocytes from peripheral blood mononuclear cells (PBMCs) obtained from healthy individuals and MS patients. We found that IL4I1 increased the relative densities of Th2 and regulatory T‐cells, while reducing Th17 cell density in healthy control (HC) samples. Furthermore, IL4I1‐treated lymphocytes promoted CNS remyelination when grafted into demyelinated spinal cord lesions in mice. We found that baseline endogenous IL4I1 expression was reduced in people with MS. However, unlike HCs, IL4I1 treatment had no significant effect on IL17 or TOB1 expression in lymphocytes derived from MS patients. These results suggest that IL4I1 skews CD4 + T‐cells to a regulatory state in healthy human lymphocytes, which may be essential for promoting remyelination. However, IL4I1 appears unable to exert its influence on lymphocytes in MS, indicating that impaired IL4I1‐mediated activity may underlie MS pathology.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are remarkably effective for treating EGFR-mutant non-small cell lung cancer (NSCLC). However, patients inevitably develop acquired drug resistance, resulting in recurrence or metastasis. It is important to identify novel effective therapeutic targets to reverse acquired TKI resistance. Bioinformatics analysis revealed that nicotinamide N-methyltransferase (NNMT) was upregulated in EGFR-TKI resistant cells and tissues via EGR1-mediated transcriptional activation. High NNMT levels were correlated with poor prognosis in EGFR-mutated NSCLC patients, which could promote resistance to EGFR-TKIs in vitro and in vivo. Mechanistically, NNMT catalyzed the conversion of nicotinamide to 1-methyl nicotinamide by depleting S-adenosyl methionine (the methyl group donor), leading to a reduction in H3K9 trimethylation (H3K9me3) and H3K27 trimethylation (H3K27me3) and subsequent epigenetic activation of EGR1 and ALDH3A1. In addition, ALDH3A1 activation increased lactic acid levels, which further promoted NNMT expression via p300-mediated histone H3K18 lactylation on its promoter. Thus, NNMT mediates the formation of a double positive feedback loop via EGR1 and lactate, EGR1/NNMT/EGR1 and NNMT/ALDH3A1/lactate/NNMT. Moreover, the combination of a small-molecule inhibitor for NNMT (NNMTi) and osimertinib exhibited promising potential for the treatment of TKI resistance in an NSCLC osimertinib-resistant xenograft model. The combined contribution of these two positive feedback loops promotes EGFR-TKI resistance in NSCLC. Our findings provide new insight into the role of histone methylation and histone lactylation in TKI resistance. The pivotal NNMT-mediated positive feedback loop may serve as a powerful therapeutic target for overcoming EGFR-TKI resistance in NSCLC. The online version contains supplementary material available at 10.1186/s12943-025-02285-y.

Global disparities in cancer prevention, detection, and treatment demand a unified international effort to reduce the disease’s burden and improve outcomes. Despite advances in chemotherapy and radiotherapy, many tumors remain resistant to these treatments. Gold nanoparticles (AuNPs) have shown promise as radiosensitizers, enhancing the effectiveness of low-energy X-rays by emitting Auger electrons that cause localized cellular damage. In this study, spherical AuNPs of 5 nm and 10 nm were characterized and tested on various cell lines, including malignant breast cells (MCF-7), non-malignant cells (CHO-K1 and MCF-10A), and human lymphocytes. Cells were treated with AuNPs and irradiated with attenuated 6 megavoltage (MV) X-rays or p(66)/Be neutron radiation to assess DNA double-strand break (DSB) damage, cell viability, and cell cycle progression. The combination of AuNPs and neutron radiation induced higher levels of γ-H2AX foci and micronucleus formation compared to treatments with AuNPs or X-ray radiation alone. AuNPs alone reduced cellular kinetics and increased the accumulation of cells in the G2/M phase, suggesting a block of cell cycle progression. For cell proliferation, significant effects were only observed at the concentration of 50 μg/mL of AuNPs, while lower concentrations had no inhibitory effect. Further research is needed to quantify internalized AuNPs and correlate their concentration with the observed cellular effects to unravel the biological mechanisms of their radioenhancement.

Methylmalonic aciduria (MMA) is an inborn error of metabolism resulting in loss of function of the enzyme methylmalonyl-CoA mutase (MMUT). Despite acute and persistent neurological symptoms, the pathogenesis of MMA in the central nervous system is poorly understood, which has contributed to a dearth of effective brain specific treatments. Here we utilised patient-derived induced pluripotent stem cells and in vitro differentiation to generate a human neuronal model of MMA. We reveal strong evidence of mitochondrial dysfunction caused by deficiency of MMUT in patient neurons. By employing patch-clamp electrophysiology, targeted metabolomics, and bulk transcriptomics, we expose an altered state of excitability, which is exacerbated by application of dimethyl-2-oxoglutarate, and we suggest may be connected to metabolic rewiring. Our work provides first evidence of mitochondrial driven neuronal dysfunction in MMA, which through our comprehensive characterisation of this paradigmatic model, enables first steps to identifying effective therapies. Subject terms: Mechanisms of disease, Metabolic disorders, Diseases of the nervous system

Calcium-regulated heat-stable protein 1 (CARHSP1) has been identified as a cold shock domain (CSD) protein family member, participating in the regulation of ribosomal translation, mRNA degradation, and the rate of transcription termination. However, there is an extremely limited understanding of the function of CARHSP1 as an RNA binding protein (RBP) in prostate cancer (PCa). The expression pattern of CARHSP1 and the correlation between the CARHSP1 expression and clinical prognosis in PCa patients were analyzed by using multiple public databases. In vitro and in vivo functional assays were conducted to assess the role of CARHSP1. The mechanisms of CARHSP1 function on IL-17RA were identified by RNA pull-down and RNA stability assays. A co-culture model of Jurkat cells and PCa cells was established to investigate the potential role of CARHSP1 in tumor immunity of PCa. CARHSP1 was highly expressed in PCa, and correlated with advanced characteristics of PCa and unfavorable prognosis in PCa patients. Moreover, knockdown of CARHSP1 significantly dampened the capacity of proliferation, migration, invasion, and immune evasion of PCa cells in vitro and in vivo. Mechanistically, the RNA-binding protein CARHSP1 selectively bound to the mRNA of IL-17RA, resulting in the increased expression of both IL-17RA mRNA and protein. Downregulating expression of CARHSP1 shortened the half-life of IL-17RA mRNA and reduced its expression. Subsequently, the downstream pathways of IL-17RA, JAK-STAT3 signaling pathway and NF-κB signaling pathway, were activated by CARHSP1 and contributed to the malignant phenotype of PCa cells. In conclusion, our results demonstrated that the increased expression of CARHSP1 in PCa is correlated with advanced clinical characteristics and unfavorable prognosis, and CARHSP1 may promote the progression of PCa through enhancing the mRNA stability of IL-17RA and activating its downstream pathways. These results suggest that CARHSP1 is an important regulator of tumor microenvironment in PCa, and CARHSP1-IL-17RA axis could be potential novel therapeutic targets for PCa. The online version contains supplementary material available at 10.1186/s13578-025-01371-4.