Human Cell[JOURNAL]
Sun
200 papers
miR-16-2-3p enhances glucocorticoid sensitivity in ulcerative colitis by targeting CREB1 and NF-κB1.
Yang T, Luo J, Tang J … +7 more , Wu J, Xia S, Li M, Huang Q, Yang G, Miao J, Zhu Y
Hum Cell · 2026 May · PMID 42201570 · Publisher ↗
In this study, we systematically investigated the role of miR-16-2-3p, a microRNA passenger strand derived from the MIR16-2 hairpin, in glucocorticoid resistance (GCR) and its underlying regulatory mechanisms. The result...
In this study, we systematically investigated the role of miR-16-2-3p, a microRNA passenger strand derived from the MIR16-2 hairpin, in glucocorticoid resistance (GCR) and its underlying regulatory mechanisms. The results showed that miR-16-2-3p expression was significantly downregulated in patients with GCR and in glucocorticoid-resistant-like inflammatory models, and was positively correlated with glucocorticoid receptor (GR) expression, accompanied by a reduced responsiveness to the glucocorticoid dexamethasone (Dex). Functional experiments demonstrated that overexpression of miR-16-2-3p enhanced the inhibitory effects of Dex on inflammatory cytokines (interleukin [IL]-1β, IL-6, IL-8, and tumour necrosis factor alpha [TNF-α]) and promoted nuclear translocation of the GR, whereas inhibition of miR-16-2-3p expression attenuated the anti-inflammatory effects of Dex. Mechanistically, cAMP response element-binding protein 1 (CREB1) was identified as a direct target of miR-16-2-3p, and CREB1 silencing promoted GR nuclear translocation and enhanced the anti-inflammatory efficacy of Dex. In addition, miR-16-2-3p further suppressed nuclear factor kappa-B (NF-κB) signalling by targeting NF-κB1 (p105), thereby synergistically strengthening the inhibitory effect of Dex on NF-κB. In vivo, overexpression of miR-16-2-3p significantly improved the pathological phenotype of dextran sulphate sodium (DSS)-induced ulcerative colitis (UC) in mice and enhanced the therapeutic effect of Dex. Our findings revealed a dual molecular mechanism by which miR-16-2-3p enhances glucocorticoid sensitivity (GCS) through targeting CREB1 and NF-κB1, providing experimental evidence for its potential as a novel therapeutic agent for GCR.
Gata1-mediated Hras transcription stimulates blood-brain barrier injury in ischemic stroke through activation of the ERK pathway.
Chen K, Chen L, Sun H … +1 more , Li B
Hum Cell · 2026 May · PMID 42189366 · Publisher ↗
Disruption of the blood-brain barrier (BBB) is an essential pathological outcome of ischemic stroke (IS). This study aimed to prove that Gata1 upregulates Hras and promotes ERK signaling, leading to BBB damage in IS. Mid...
Disruption of the blood-brain barrier (BBB) is an essential pathological outcome of ischemic stroke (IS). This study aimed to prove that Gata1 upregulates Hras and promotes ERK signaling, leading to BBB damage in IS. Middle cerebral artery occlusion (MCAO) was used for in vivo modeling, and cerebrovascular endothelial cell-specific adeno-associated viruses were used for Gata1/Hras expression manipulation. TTC staining, Evans blue extravasation assay, and Western blot analysis were conducted to investigate the role of Gata1 and Hras in BBB injury. Mouse bEnd.3 cells were exposed to oxygen-glucose deprivation (OGD), and lentivirus-mediated genetic interventions were performed. Viability, lactate dehydrogenase release, and BBB permeability were assessed in bEnd.3 cells. The regulation of Gata1 on Hras was examined using ChIP-qPCR and a dual-luciferase assay. Gata1 was upregulated in mice after MCAO, and Gata1 knockdown reduced cerebral infarction and decreased BBB leakage in mice. Gata1 knockdown also alleviated OGD-induced BBB permeability and bEnd.3 cell injury. Gata1 transcriptionally activated Hras and promoted the ERK signaling. Hras reactivation reversed BBB injury in MCAO mice and BBB permeability and bEnd.3 cell injury alleviated by Gata1 knockdown. Overall, Gata1 transcriptionally upregulates Hras expression and activates the ERK signaling to exacerbate BBB dysfunction in mice after MCAO.
NOTCH3 signal activation by its extracellular domain accumulation in an iPSC line newly established from a CADASIL patient.
Sun R, Zhao Z, Che N … +6 more , Liu N, Ji X, Li A, Wang F, Shang J, Zhang J
Hum Cell · 2026 May · PMID 42177738 · Publisher ↗
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic cerebral small-vessel disease caused by NOTCH3 mutations, yet its pathogenic mechanisms re...
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic cerebral small-vessel disease caused by NOTCH3 mutations, yet its pathogenic mechanisms remain incompletely understood due to limited disease models. The NOTCH3 R544C mutation is a prevalent hotspot in East Asian populations, but patient-derived iPSC models are lacking. Here, we generated an iPSC line from peripheral blood mononuclear cells of a middle-aged CADASIL patient carrying a heterozygous NOTCH3 c.1630C > T (p.Arg544Cys, R544C) mutation using a Sendai virus (SeV)-based reprogramming approach. The iPSCs exhibited typical morphology, normal 46, XY karyotype, expressed pluripotency markers (OCT4, NANOG, TRA-1-60, SSEA-4), and cleared SeV vectors after passaging. They differentiated into derivatives of all three germ layers, and STR analysis confirmed donor identity. Functionally, CADASIL iPSCs showed abnormal accumulation of the NOTCH3 extracellular domain (NOTCH3ECD) with unchanged NOTCH3 full-length and intracellular domain levels, and upregulation of canonical downstream genes HEY1, NRARP, and HES1, indicating activation of the NOTCH3 signaling pathway. This study establishes and characterizes a NOTCH3 R544C patient-derived iPSC line, providing a valuable model for investigating CADASIL pathogenesis and potential therapeutic strategies, with novel insights into early NOTCH3ECD accumulation and pathway activation.
METTL14 promotes trophoblast dysfunction by elevating SZRD1 expression in an m6A-dependent manner.
Ye Q, Deng L
Hum Cell · 2026 May · PMID 42133253 · Publisher ↗
Preeclampsia, a common hypertensive pregnancy disorder associated with shallow trophoblast invasion, is a leading cause of perinatal and maternal mortality worldwide. Many studies have indicated that genes are differenti...
Preeclampsia, a common hypertensive pregnancy disorder associated with shallow trophoblast invasion, is a leading cause of perinatal and maternal mortality worldwide. Many studies have indicated that genes are differentially expressed between normal and diseased states. This study found that SUZ RNA binding domain containing 1 (SZRD1) expression was increased in placenta from preeclamptic pregnancies. However, the role and mechanism of SZRD1 in patients with preeclampsia are unclear. Gene expression was determined by RT-qPCR and Western blot. Cell proliferation, apoptosis, migration, invasion, and angiogenesis were assessed using EdU, flow cytometry, wound healing, transwell, and tube formation assays. The interaction between Methyltransferase-like 14 (METTL14) and SZRD1 was analyzed using methylated RNA immunoprecipitation (MeRIP)-qPCR and RIP assay. SZRD1 and METTL14 were highly expressed in placenta from preeclamptic pregnancies (n = 30) compared with normal tissues (n = 30) (p < 0.001). By using HTR-8/SVneo trophoblast cells, the silencing of SZRD1 could promote cell proliferation (p < 0.01), migration (p < 0.05), invasion (p < 0.01), angiogenesis (p < 0.01), and hinder cell apoptosis (p < 0.01) in vitro. At the molecular level, METTL14 enhanced the stability of SZRD1 mRNA via m6A methylation. The METTL14-mediated stabilization of SZRD1 mRNA could exacerbate the dysfunction in HTR-8/SVneo cells associated with preeclampsia. These findings highlight the potential of targeting the METTL14/SZRD1 axis as a therapeutic strategy for managing preeclampsia.
Bisphosphoglycerate mutase is involved in glucose metabolism and progression of nonalcoholic fatty liver disease based on liver organoids.
Zhou Z, Zheng X, Chen X … +4 more , Xie M, Du F, Lin Z, Shi X
Hum Cell · 2026 May · PMID 42126781 · Publisher ↗
This study seeks to investigate the underlying mechanism of glycolytic key gene bisphosphoglycerate mutase (BPGM) in nonalcoholic fatty liver disease (NAFLD). qRT-PCR and immunohistochemistry were utilized to detect BPGM...
This study seeks to investigate the underlying mechanism of glycolytic key gene bisphosphoglycerate mutase (BPGM) in nonalcoholic fatty liver disease (NAFLD). qRT-PCR and immunohistochemistry were utilized to detect BPGM levels in clinical NAFLD samples. HepG2 cells and liver organoids were treated with free fatty acid. (FFA). The role of BPGM in NAFLD was explored at cellular, organoid, and animal levels. Metabolomics was performed to analyze differential metabolites and metabolic pathways. Furthermore, we examined the regulatory mechanisms of BPGM by HIF-1α in NAFLD. Results indicated that high expression of BPGM in NAFLD samples was correlated with NAFLD progression. Moreover, Severe group had higher BPGM expression than Mild group. FFA treatment induced time-dependent steatosis and BPGM upregulation in HepG2 cells and liver organoids, whereas BPGM knockdown attenuated lipid accumulation, cellular injury, and oxidative stress. At the animal level, knockdown of BPGM reversed high-fat diet (HFD) induced lipid accumulation and liver tissue injury. Metabolomics studies showed significant changes of metabolic pathways including glycolysis/gluconeogenesis and pyruvate metabolism. Verification experiment showed FFA increased pyruvic acid levels, and knockdown of BPGM decreased pyruvic acid levels. Pyruvic acid further reversed the changes in NAFLD progression caused by BPGM knockdown at the cellular and organoid levels. Finally, HIF-1α regulated the expression of BPGM in NAFLD. Together, our findings suggest that BPGM contributes to abnormal glucose metabolism and promotes hepatic steatosis, thereby driving NAFLD progression.
NR1H4 downregulation facilitates abnormal cell proliferation contributing to IgA nephropathy pathogenesis, with potential clinical implications.
Li X, Yang W, Sun C
Hum Cell · 2026 May · PMID 42105136 · Publisher ↗
IgA nephropathy (IgAN) is a common glomerulonephrites worldwide. We herein aimed to investigate the pathogenic mechanisms underlying IgAN and to identify hub targets. The IgAN-related datasets were derived from the Gene...
IgA nephropathy (IgAN) is a common glomerulonephrites worldwide. We herein aimed to investigate the pathogenic mechanisms underlying IgAN and to identify hub targets. The IgAN-related datasets were derived from the Gene Expression Omnibus database. Hub targets were identified by integrating differentially expressed gene (DEG) analysis and multiple protein-protein interaction (PPI) network algorithms. Functional enrichment and immune landscape analyses were conducted to explore the functional impacts of the hub targets. An IgAN cell model was employed to confirm the hub gene expression and its effect on cell proliferation in vitro. Drugs targeting the hub gene were validated via molecular docking. By integrating DEG and multiple PPI network algorithms, NR1H4 was significantly downregulated in IgAN comparing to control samples, which was successfully validated in multiple datasets, clinical cohort, and IgAN cell model. A total of 48 pathways were significantly enriched in both NR1H4 low vs. high expression groups and IgAN vs. control groups. Moreover, NR1H4 overexpression significantly inhibited the abnormal cell proliferation of IgA1-induced HMCs in vitro. NR1H4 showed great clinical potential in IgAN, particularly in terms of diagnostic value (AUC > 0.7) and as a drug target (e.g., the promising drug like obeticholic acid). In conclusion, NR1H4 downregulation probably contributed to the development of IgAN by promoting abnormal cell proliferation, highlighting its considerable clinical potential in the management strategy of IgAN.
Deciphering the immunological landscape of HR + metastatic breast cancer: insights from single-cell transcriptomics.
He L, Zhao Q, Chen Z … +5 more , He L, Qi Z, Wu J, Zhou K, Cui Y
Hum Cell · 2026 May · PMID 42101520 · Full text
Breast cancer remains the leading cause of cancer-related mortality among women worldwide, primarily due to metastatic complications. The immune components of the tumor microenvironment (TME) significantly influence meta...
Breast cancer remains the leading cause of cancer-related mortality among women worldwide, primarily due to metastatic complications. The immune components of the tumor microenvironment (TME) significantly influence metastatic progression. The objective of this study was to uniquely characterize the TME of hormone receptor-positive (HR +) breast cancer with a focus on ovarian metastasis using single-cell RNA sequencing. We delineated the cellular architecture of breast cancer tissues. A total of 9 cell types in 18 clusters were identified, including T cell, B cell and plasma, macrophage, neutrophil, fibroblast, macrophage, endothelial, basal, luminal, SMC (smooth muscle cells) and proliferation cells. Furthermore, macrophages were divided into tumor-associated macrophages and monocyte macrophages, with detailed marker gene analysis. Key statistical findings include the identification of five critical genes (GPR183, BHLHE41, CD83, SLC25A37, and SELL) associated with macrophage functionality. In vivo validation using immunohistochemistry on clinical samples from 10 breast cancer patients with ovarian metastases confirmed that GPR183, BHLHE41, and CD83 were highly expressed in tumor tissues, while SLC25A37 and SELL were highly expressed in adjacent normal tissues. Furthermore, survival analysis correlated the expression levels of these genes with patient outcomes, thus presenting potential prognostic biomarkers. Our study contributes to a deeper insight of the tumor microenvironment in HR + metastatic breast cancer, and offers potential targets for developing novel therapeutic interventions aimed at mitigating metastatic progression and improving clinical outcomes for HR + breast cancer patients.
Transcriptomic landscape of oral potentially malignant disorders: a meta-analysis approach.
Vasudevan V, Siddappa G, Sam RE … +10 more , Madhumathi HK, Thomas A, Sunny SP, Shetty V, Bhushan V, Dokhe Y, Pillai V, Birur P, Kuriakose MA, Suresh A
Hum Cell · 2026 May · PMID 42082814 · Publisher ↗
Early detection of potentially malignant and malignant lesions in the oral cavity is mandatory for reduction in oral cancer incidence, detection at an early stage and improving survival. The objective of this study was t...
Early detection of potentially malignant and malignant lesions in the oral cavity is mandatory for reduction in oral cancer incidence, detection at an early stage and improving survival. The objective of this study was to catalogue the transcriptomic pattern across pre-cancerous stages, identify the major signalling processes, and infiltrating immune cell subtypes using the integrated, multi-dataset, meta-analysis approach. Following a search in the public databases, a total of five datasets were included in the study. The patient samples were stratified to identify the changes in high-grade dysplasia (HGD, moderate/severe dysplasia) as opposed to low-risk lesions (LRL, benign/OPMD) and low-grade dysplasia (LGD). Weighted gene co-expression network analysis (WGCNA; p < 0.05, |Correlation coefficient|:0.3) integrated with differential gene expression (DEG; p < 0.05, Fold change: 1.5) analysis revealed alterations in low-to-high-risk lesions included changes in DNA replication, loss of cell adhesions converging on a hub panel of tumor promoter/suppressors. The shift to high grade dysplasia was marked by enhanced immune/cytokine signalling with hub-gene network driving metabolic regulation, immune evasion, and ECM-stroma interaction. In transformed lesions, the immune-modulatory environment persisted, now accompanied by a notable downregulation of interferon (IFN) signalling. Interferon-inducible network and stemness induction were key hub gene networks. Digital cytometric analysis indicated specific enrichment of T regulatory cells and dendritic cells in differentiating the grades of dysplasia, while T helper cells were specific for malignant transformation. Collectively, these results indicate the role of immune surveillance during oral carcinogenesis. The distinct molecular/immunological shifts during dysplastic progression and malignant transformation represent critical milestones in oral potentially malignant disorder (OPMD) progression, offering actionable insights for prognosis, prevention, and therapeutic intervention.
Heterogeneity of HTLV-1 proviral integration sites and internal structures in the ATL cell line MT-1.
Izaki M, Hashikura Y, Umekita K … +2 more , Umeki K, Miyazaki T
Hum Cell · 2026 Apr · PMID 42062604 · Full text
Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL). The ATL-derived cell line MT-1 is used to study HTLV-1 biology and leukemogenesis. However, the proviral integration sites and internal stru...
Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL). The ATL-derived cell line MT-1 is used to study HTLV-1 biology and leukemogenesis. However, the proviral integration sites and internal structures of HTLV-1 are not comprehensively characterized in MT-1 cells. We analyzed two independently maintained MT-1 cell lines (MT-1 J and MT-1 M) using long PCR, quantitative PCR-based proviral load analysis, inverse long PCR, inverse PCR, integration site-specific PCR, direct sequencing, and Rapid Amplification of Integration Site without Interference by Genomic DNA contamination. Long PCR and proviral load analyses demonstrated that MT-1 cells harbor multiple full-length and defective HTLV-1 proviruses. MT-1 J cells exhibited reduced proviral load in the pX region, suggesting the presence of pX-lacking proviruses. Inverse long PCR and inverse PCR revealed at least five proviral integration sites in MT-1 J cells; MT-1 M cells contained three. Site-specific PCR confirmed the differential preservation of integration sites. Sequence analysis revealed two full-length proviruses and three type I defective proviruses with distinct internal deletions, including an unreported provirus with a large deletion encompassing pX. Rapid Amplification of Integration Site without Interference by Genomic DNA contamination identified major proviral clones shared between MT-1 J and MT-1 M cells, while revealing differences in clone frequencies and minor integration sites. The MT-1 cell line is a polyclonal population containing multiple full-length and defective HTLV-1 proviruses. Its proviral composition can change during long-term in vitro passaging. This heterogeneity should be considered when interpreting results obtained using MT-1 cells in HTLV-1 and ATL research.
Establishment and characterization of a novel HBV-integrated hepatic sarcomatoid carcinoma cell line.
Dai J, Cao F, Yang Z … +4 more , Dong K, Huang X, Bian X, Liu Y
Hum Cell · 2026 Apr · PMID 42014525 · Publisher ↗
Hepatic sarcomatoid carcinoma (HSC) is a rare and highly aggressive liver malignancy with an extremely poor prognosis. The lack of well-validated cellular models has severely limited mechanistic and translational researc...
Hepatic sarcomatoid carcinoma (HSC) is a rare and highly aggressive liver malignancy with an extremely poor prognosis. The lack of well-validated cellular models has severely limited mechanistic and translational research on this disease. In this study, we established and comprehensively characterized a novel HSC cell line, designated PUMC-LICA3. This cell line was derived from surgically resected tumor tissue of a 58-year-old male patient and has been continuously cultured for more than 40 passages, with a population doubling time of 51.77 h and an epithelial-like morphology. Long-read sequencing identified HBV DNA integration at chromosome 17p11.2 without detectable covalently closed circular DNA (cccDNA) or viral antigen expression, indicating a non-replicative viral status. PUMC-LICA3 exhibited 100% tumorigenicity in NOD/SCID mice. Xenograft tumors displayed immunohistochemical features consistent with sarcomatoid carcinoma, characterized by the co-expression of epithelial markers (CK and CK19) and the mesenchymal marker vimentin. E-cadherin expression was patchy, with partial loss in subsets of tumor cells, whereas N-cadherin was diffusely expressed. Notably, PUMC-LICA3 exhibited a high epithelial-mesenchymal transition (EMT) score and, among 22 hepatocellular carcinoma (HCC), clustered most closely with JHH-6 and SNU-387. Drug sensitivity assays showed that the cell line was sensitive to cisplatin, doxorubicin and sorafenib, but resistant to 5‑fluorouracil. Whole-exome sequencing (WES) analysis revealed that the cell line largely preserved the genetic characteristics of its parental tumor throughout long-term culture. In conclusion, the newly established PUMC-LICA3 cell line represents a reliable and valuable experimental model for investigating the biological characteristics and therapeutic strategies of hepatic sarcomatoid carcinoma.
Culture-dependent baseline states and drug response programs in myxofibrosarcoma models across 2D and 3D systems.
Yoshimatsu Y, Shiota Y, Kondo T
Hum Cell · 2026 Apr · PMID 42012768 · Publisher ↗
Myxofibrosarcoma (MFS) is a rare soft-tissue sarcoma with limited systemic therapy options, necessitating preclinical platforms that better simulate clinical drug responses. We investigated how 2D monolayers versus 3D sp...
Myxofibrosarcoma (MFS) is a rare soft-tissue sarcoma with limited systemic therapy options, necessitating preclinical platforms that better simulate clinical drug responses. We investigated how 2D monolayers versus 3D spheroids shape the baseline transcriptome and doxorubicin (DOX)-responsive programs across six patient-derived MFS cell lines. RNA sequencing revealed that 3D culture induces a distinct transcriptomic state characterized by the enrichment of microenvironment-associated stress programs, such as hypoxia, inflammatory/NF-κB signaling, and glycolysis, alongside the suppression of proliferation-related pathways. Although the global DOX-induced transcriptional response was highly environment-dependent, we identified a robust core of six regulators-MCRIP1, FGF12, HGF, EMSY, FZD2, and SECISBP2-whose transcriptional changes consistently correlated with cell survival rates across both 2D and 3D geometries. These genes are involved in transcriptional plasticity, redox homeostasis, and bypass survival signaling, providing a mechanistic basis for DOX resistance that transcends culture conditions. Our findings demonstrate that while culture geometry is a critical determinant of the MFS transcriptome, a robust set of environment-agnostic regulators dictates DOX efficacy. Integrating 3D systems with these specific transcriptomic readouts enhances the interpretability of drug screenings and supports the prioritization of rational therapeutic combinations for this rare sarcoma.
Generation of a human-induced pluripotent stem cell line from a retinitis pigmentosa patient carrying biallelic mutations in EYS gene.
Kim J, Yu J, Kim D … +4 more , Shin B, Kim J, Park YS, Kim KP
Hum Cell · 2026 Apr · PMID 42001345 · Publisher ↗
Retinitis pigmentosa (RP) is a hereditary retinal disorder characterized by progressive degeneration of photoreceptor cells in the retina, leading to gradual vision loss. Symptoms of RP typically begin with night blindne...
Retinitis pigmentosa (RP) is a hereditary retinal disorder characterized by progressive degeneration of photoreceptor cells in the retina, leading to gradual vision loss. Symptoms of RP typically begin with night blindness and progressive loss of peripheral vision, eventually leading to severe tunnel vision and, in advanced stages, loss of central vision or complete blindness. To date, no effective therapeutic strategies have been developed to halt disease progression, mitigate vision loss, or achieve a complete cure, and currently available disease models have limitations in fully recapitulating the human disease phenotype. In this study, we generated a human induced pluripotent stem cell (hiPSC) line, CUKi001-A, from fibroblasts of a 20-year-old male patient with EYS-associated RP using lentiviral delivery of reprogramming factors OCT4, SOX2, KLF4, and c-MYC. The CUKi001-A iPSC line carried heterozygous missense mutations in exon 16 (c.2528G > A, p.G843E) and exon 37 (c.7382 T > C, p.L2461S) of the EYS gene, consistent with its parental fibroblasts. The established iPSC line exhibited typical iPSC morphology, a normal karyotype, expression of key pluripotency markers, and the ability to differentiate into derivatives of all three germ layers. The hiPSC line established in this study provides a valuable platform for investigating the pathogenic mechanisms of EYS-associated RP and for developing potential therapeutic strategies.
Human peritoneal CCR2CRIg macrophage subset exhibits embryonic origin-like phenotypes.
Takahashi N, Habash SA, Komohara Y … +9 more , Usuki S, Yasunaga KI, Hino S, Abdelnaser RA, Einarsdottir T, Nomura T, Yonemura A, Ishimoto T, Suzu S
Hum Cell · 2026 Apr · PMID 41991819 · Publisher ↗
Recent studies in mouse models have demonstrated that macrophages in adult tissues are maintained not only by the differentiation of bone marrow-derived monocytes but also by the proliferation of macrophages originating...
Recent studies in mouse models have demonstrated that macrophages in adult tissues are maintained not only by the differentiation of bone marrow-derived monocytes but also by the proliferation of macrophages originating from the yolk sac or fetal liver. However, the extent to which this paradigm shift occurs in human tissues is not fully understood. In this study, we detected a human peritoneal macrophage subset that exhibited embryonic origin-like phenotypes. Macrophages in the ascites of patients with gastric cancer were divided into CCR2 and CCR2 subsets, the ratios of which varied among donors. The gene expression profiles of these subsets were similar to those of the macrophage subsets in the heart. CRIg was recently reported as a marker for distinguishing between two macrophage subsets in the ascites of patients with cirrhosis. CCR2 and CCR2 subsets expressed high and low levels of CRIg, respectively. Importantly, the CCR2CRIg subset expressed the cell proliferation marker Ki67 and the recently proposed core markers (TIMD4, LYVE1, and FOLR2) of embryo-derived macrophages at higher levels than the CCR2CRIg subset. Moreover, many other markers shared by TIMD4LYVE1FOLR2 macrophages in heart, lung, kidney, and liver exhibited similar expression patterns in the peritoneal CCR2CRIg subset. These results suggest that the CCR2CRIg subset in the peritoneal cavity contains macrophages with embryonic origin.
Pathogenesis and therapeutic strategies for neuropsychiatric lupus centered on innate immune activation.
Nagata W, Ishizuka T
Hum Cell · 2026 Apr · PMID 41989680 · Full text
Neuropsychiatric systemic lupus erythematosus (NPSLE) is a serious central nervous system complication of systemic lupus erythematosus (SLE) that markedly reduces patient quality of life. Despite its clinical importance,...
Neuropsychiatric systemic lupus erythematosus (NPSLE) is a serious central nervous system complication of systemic lupus erythematosus (SLE) that markedly reduces patient quality of life. Despite its clinical importance, the underlying mechanisms remain incompletely defined, and effective treatments are limited. In this review, we synthesize preclinical and clinical evidence that aberrant activation of innate immunity by self-nucleic acids and consequent overproduction of Type I interferons (IFN-I) constitute a central pathogenic axis in NPSLE. IFN-I and other inflammatory mediators promote disruption of the blood-brain barrier (BBB), enabling entry of autoantibodies, cytokines, and immune cells into the brain. These factors, together with damage-associated molecular patterns, activate microglia and astrocytes, driving sustained neuroinflammation that provokes synaptic loss, neurotransmitter dysregulation, excitotoxic neuronal injury, impaired neurogenesis, and mitochondrial dysfunction-mechanisms that underlie cognitive impairment, mood disorders, and other neuropsychiatric manifestations. We review therapeutic strategies targeting each step of this cascade, including blockade of IFN-I signaling (e.g., anifrolumab), inhibition of endosomal nucleic acid sensing (TLR antagonists), cytokine and JAK inhibition, modulation of microglial function (CSF1R inhibitors), and approaches to protect or restore BBB integrity (e.g., statins). Finally, we discuss biomarker-guided patient stratification and trial designs necessary to address NPSLE heterogeneity and accelerate the development of personalized therapies. By elucidating the cellular responses of the neurovascular unit to innate immune insults, this review provides a molecular framework for developing targeted therapies for NPSLE.
Extracellular vesicle-derived CDCP1 promotes chemoresistance and macrophage polarization in breast cancer.
Liu Y, Ma L, Zhu T … +2 more , Wu D, Liu Y
Hum Cell · 2026 Apr · PMID 41975113 · Publisher ↗
Breast cancer derived extracellular vesicles (EVs) mediate tumor progression through surface protein-dependent intercellular communication; however, their molecular heterogeneity remains poorly characterized. In this stu...
Breast cancer derived extracellular vesicles (EVs) mediate tumor progression through surface protein-dependent intercellular communication; however, their molecular heterogeneity remains poorly characterized. In this study, we employed a proximity-dependent barcoding assay (PBA) together with patient-derived organoid (PDO) models and identified CDCP1 as a key driver of EV-mediated oncogenesis. PBA-based surface proteomics revealed CDCP1 as the most upregulated protein in breast cancer-derived EVs compared with EVs from normal tissues. Clinical validation confirmed elevated CDCP1 expression in tumor tissues and matched EVs. PDOs generated from fresh clinical specimens recapitulated CDCP1 expression levels of the parental tumors and secreted CDCP1-enriched EVs. Functional experiments showed that CDCP1-knockdown EVs suppressed PDO proliferation and sensitized tumors to chemotherapy. Mechanistically, CDCP1-positive EVs promoted macrophage polarization toward an M2 phenotype, accompanied by upregulation of IL-10 and TGF-β and CCL22. Multiplex immunofluorescence confirmed that CDCP1-high tumors exhibited increased co-localization of CD68⁺ and CD163⁺ macrophages. These results establish CDCP1 as a master regulator of EV driven breast cancer progression, linking surface proteome remodeling to chemo-resistance and immunosuppressive microenvironment reprogramming. The integration of single-EV profiling and PDO modeling establishes a translational framework for targeting CDCP1 as a promising therapeutic target and a candidate biomarker for future liquid biopsy development in aggressive breast cancer subtypes.
Ethanol-induced NINJ1 oligomerization might contribute to the lytic death of granulosa cells in PCOS.
Berkel C
Hum Cell · 2026 Apr · PMID 41973354 · Publisher ↗
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Exploring the role of protein homeostasis regulation in glycolysis in head and neck tumors.
Xia T, Jiang K, Huang Q … +3 more , Luo Y, Chen L, Xu D
Hum Cell · 2026 Apr · PMID 41954805 · Publisher ↗
Metabolic reprogramming is a hallmark of cancer. Tumor cells adapt to their environment by modulating glucose, lipid, and amino acid metabolism to supply raw materials for rapid growth and enhance treatment resistance. A...
Metabolic reprogramming is a hallmark of cancer. Tumor cells adapt to their environment by modulating glucose, lipid, and amino acid metabolism to supply raw materials for rapid growth and enhance treatment resistance. Among these, glucose metabolic reprogramming is particularly critical. In head and neck tumor cells, glycolysis-derived intermediate metabolites provide biosynthetic precursors and energy necessary for growth, sustaining proliferation and invasion. Additionally, these metabolites can remodel the tumor microenvironment, modulate signaling pathways, and alter tumor phenotypes, further promoting chemoresistance and radioresistance. Protein homeostasis (proteostasis) refers to the dynamic balance of cellular processes involving protein synthesis, folding, modification, transport, and degradation, which is essential for maintaining normal physiological functions. This review aims to explore how proteostasis-regulated degradation pathways-specifically the ubiquitin-proteasome system (UPS) and autophagy-lysosome pathway-modulate glycolysis in head and neck tumors, thereby influencing tumor proliferation and invasion. These insights may provide a theoretical foundation for overcoming treatment resistance and improving prognosis, while also opening new avenues for future therapeutic research in head and neck oncology.
Pathological and therapeutic implications of Notch overexpression in claudin-low breast cancers.
Yadav R, Goel S, Kaur D … +4 more , Kumari L, Dahiya D, Bal A, Bhatia A
Hum Cell · 2026 Apr · PMID 41951892 · Publisher ↗
Claudin-low breast cancers (BCs), representing approximately 1.5-14% of all BCs, are characterized by high aggressiveness, enriched cancer stem cell (CSC) population, and poor prognosis. Despite the established role of N...
Claudin-low breast cancers (BCs), representing approximately 1.5-14% of all BCs, are characterized by high aggressiveness, enriched cancer stem cell (CSC) population, and poor prognosis. Despite the established role of Notch signaling in mammary gland development and BC progression, its status in claudin-low BCs remains inadequately explored. In this study, Notch pathway activation was evaluated in BC cell lines and 107 patient samples. Claudin-low subtype exhibited elevated Notch activity. Notch1 was observed to be the predominant receptor in the above subtype, whereas Notch3 was predominant in the claudin-high cancers. Notch1 and HES1 expression showed a significant inverse correlation with claudins 3, 4, and 7, and were positively associated with aggressive tumor features including high Ki67 index, higher grade, and increased metastasis. Immunohistochemical analysis further confirmed a correlation between nuclear Notch1 (N1ICD) expression and claudin-low status, supporting its potential as a biomarker for identification of aggressive BC. Combined treatment with celecoxib (10 µM) and doxorubicin (1 µM) in claudin-low cells not only significantly inhibited Notch signaling and claudin expression, but also suppressed viability, proliferation, migration, and BCSC populations. Since Notch signalling may be an essential factor in these latter events, our findings suggest that Notch1/N1ICD can serve as therapeutic targets for the better management of claudin-low BCs. However, validation of the same requires detailed functional studies involving modulation of each type of Notch receptor or other players involved in Notch signaling using more robust approaches.
AKR1B10 drives hepatic steatosis and inflammation in metabolic dysfunction-associated steatotic liver disease via PI3K/AKT-mediated autophagy suppression.
Nie N, Tian J, Dong X
Hum Cell · 2026 Apr · PMID 41945278 · Publisher ↗
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent metabolic disorder marked by excessive hepatic lipid accumulation, in which impaired autophagy plays a critical role. Aldo-keto reductase fa...
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent metabolic disorder marked by excessive hepatic lipid accumulation, in which impaired autophagy plays a critical role. Aldo-keto reductase family 1 member B10 (AKR1B10) has been implicated in lipid metabolism; however, its regulatory function in MASLD pathogenesis remains poorly understood. This study aimed to elucidate the role of AKR1B10 in MASLD progression and the underlying molecular mechanisms. Differentially expressed genes were identified using the GSE135251 dataset. Serum and liver tissue samples were obtained from 28 patients with MASLD and 28 healthy controls. In vivo, a MASLD mouse model was established by feeding a high-fat diet (HFD), while in vitro, lipid accumulation was induced in AML-12 hepatocytes by treatment with free fatty acids (FFA). This study found that AKR1B10 expression was significantly upregulated in MASLD patients, HFD-fed mice, and FFA-treated AML-12 cells. Silencing AKR1B10 alleviated lipid accumulation, inflammation, and autophagic impairment in vitro, and attenuated hepatic steatosis and metabolic dysfunction in vivo. Mechanistically, AKR1B10 knockdown suppressed PI3K/AKT pathway activation, thereby ameliorating lipid deposition, inflammation, and autophagic dysfunction. Conversely, treatment with 740Y-P, a PI3K agonist, reversed these protective effects and exacerbated MASLD progression. Our findings demonstrates that AKR1B10 promotes MASLD progression through activation of the PI3K/AKT signaling pathway, contributing to dysregulated lipid metabolism, inflammation, and autophagy inhibition. These findings suggest that targeting AKR1B10 may represent a novel therapeutic strategy for MASLD.
Induction of activating transcription factor 3 (ATF3) in the cerebral cortex of a mouse model of blast-induced traumatic brain injury.
Endo A, Satoh Y, Koga M … +12 more , Nagata W, Yokochi K, Asai F, Ebihara A, Tsuru T, Araki Y, Kashitani M, Toda H, Ito N, Kawasaki M, Ishizuka T, Wada K
Hum Cell · 2026 Apr · PMID 41944912 · Full text
Traumatic brain injury (TBI) is a leading cause of long-term disabilities and mortality worldwide. Blast-induced TBI (bTBI) is the injury most commonly sustained by military personnel, but the pathomechanisms are largely...
Traumatic brain injury (TBI) is a leading cause of long-term disabilities and mortality worldwide. Blast-induced TBI (bTBI) is the injury most commonly sustained by military personnel, but the pathomechanisms are largely unknown. Recently, accumulating evidence has suggested that neuroinflammation, characterized by the activation of microglia and astrocytes and elevated production of inflammatory mediators such as interleukins, cytokines, and chemotactic cytokines (chemokines), is a key pathological feature in bTBI. Therefore, controlling excessive neuroinflammation is critical to improve long-term neurological outcomes after bTBI, so understanding the mechanism of the neuroinflammation in bTBI is of significant interest. Activating transcription factor 3 (ATF3) is one of the most important transcription factors that regulate local and systemic inflammation in multiple pathophysiological processes such as cardiovascular disease, dementia, and ischemia/reperfusion-induced damage. Recently, ATF3 has attracted much attention for involvement in the neuroinflammatory response, by regulating the production of neuroinflammatory mediators, in a weight-drop-based TBI model. In this model, the upregulation of Atf3 messenger ribonucleic acid (mRNA) levels was rapidly induced with the strongest increase at 1-2 h and decline by 4 h post-injury. However, there is little information about ATF3 in bTBI, and thus, the present study examined the expression of ATF3 in a mouse bTBI model. We here show the significant upregulation of Atf3 mRNA was not observed in the cerebral cortex at 2 h post-exposure. However, the upregulation was observed at 5 days post-injury. Our results suggest robust differences in time course of neuroinflammation between other non-blast and blast TBIs.
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