Human Cell[JOURNAL]
Sun
200 papers
Vascular reprogramming in cancer: engineering the tumor microenvironment.
Nishimura Y
Hum Cell · 2026 Jul · PMID 42402079 · Publisher ↗
Tumor vasculature has traditionally been viewed as structurally and functionally abnormal and, therefore, is primarily targeted for inhibition. However, emerging evidence from vascular biology, regenerative medicine, and...
Tumor vasculature has traditionally been viewed as structurally and functionally abnormal and, therefore, is primarily targeted for inhibition. However, emerging evidence from vascular biology, regenerative medicine, and bioengineering challenges this paradigm, demonstrating that blood vessels actively instruct and shape the tumor microenvironment. Here, we propose that tumor vasculature functions as a dynamic and programmable interface that regulates cancer progression and define vascular reprogramming as a therapeutic strategy to actively redesign vascular structure, function, and signaling to control the tumor ecosystem. By integrating recent advances in endothelial cell heterogeneity, vascular niche biology, and multiscale modeling, we illustrate how tumor vessels govern cancer stemness, immune-cell trafficking, and metabolic adaptation, positioning the vasculature as a central regulatory hub rather than a passive conduit. We further highlight enabling technologies, including vascularized organoids, organ-on-a-chip systems, and iPSC-derived vasculature, that enable the precise reconstruction and manipulation of human vascular microenvironments, providing unprecedented opportunities to experimentally control vascular dynamics. Importantly, we distinguish vascular reprogramming from conventional anti-angiogenic and normalization strategies, emphasizing its potential to achieve sustained and integrative control of the tumor microenvironment. By modulating vascular permeability, perfusion, and immunoregulatory signaling, this approach enhances drug delivery, improves immune infiltration, and increases therapeutic sensitivity. Finally, we discuss the key challenges for clinical translation, including safety, scalability, and model limitations, and highlight future directions driven by spatial omics and artificial intelligence. Collectively, this framework establishes tumor vasculature as a designable therapeutic interface and advances a new paradigm in cancer therapy: not merely targeting the tumor microenvironment but engineering it through vascular control.
MiR-7-5p suppresses TGF-β-induced glycolysis and proliferation in intrahepatic cholangiocarcinoma by targeting MyD88.
Tang Y, Tang Z, Liu R … +7 more , Xie S, Chen B, Huang T, Huang X, Xie D, Zhang Q, Tang Y
Hum Cell · 2026 Jul · PMID 42400723 · Publisher ↗
Intrahepatic cholangiocarcinoma (ICC) is an insidious and aggressive malignancy with poor prognosis. Our previous research has suggested that miR-7-5p modulates the ICC cell phenotype by targeting MyD88; however, its dow...
Intrahepatic cholangiocarcinoma (ICC) is an insidious and aggressive malignancy with poor prognosis. Our previous research has suggested that miR-7-5p modulates the ICC cell phenotype by targeting MyD88; however, its downstream molecular mechanisms remain poorly elucidated. Considering that TGF-β signaling and aerobic glycolysis provide a favorable growth environment for tumors, this study aims to explored the relationship between the miR-7-5p/MyD88 axis and these metabolic characteristics. Bioinformatics methods were used to analyze the MyD88 expression in the GSE107943, and inferred its association with TGF-β signaling activity and glycolysis scores. Next, a series of experiments was conducted to evaluate the biological functions of MyD88 and miR-7-5p, with a TGF-β activator applied to elucidate potential mechanisms. A subcutaneous xenograft mouse model was used for in vivo validation. MyD88 expression was highly expressed in ICC samples, and its levels were positively correlated with TGF-β signaling activity and glycolysis scores. MyD88 knockdown attenuated the viability, migration, and glycolysis of ICC cells, thereby inhibiting tumor growth in vivo. Furthermore, MyD88 acted in a TGF-β-dependent manner, and TGF-β activation reversed the effects of MyD88 knockdown on malignant phenotype. Experiments also showed that MyD88 downregulation was caused by miR-7-5p, and then MyD88 overexpression reversed the suppressive effect of miR-7-5p on glycolysis. Collectively, miR-7-5p specifically targets MyD88, weakening glycolysis in ICCs by reducing TGF-β signaling activity, thus exerting an inhibitory effect on ICC.
Bone marrow mesenchymal stem cell-derived exosomes exert therapeutic effects on inflammatory bowel disease through miR-148a-3p/Ets-1-dependent inhibition of pyroptosis.
Zhang F, Song J, Zhang Y … +7 more , Hu H, Zhou P, Xu C, Zhan M, Hou A, Lin X, Shen W
Hum Cell · 2026 Jul · PMID 42390648 · Publisher ↗
Inflammatory bowel disease (IBD) is a non-specific chronic inflammatory condition of the gastrointestinal tract, characterized by damage to intestinal epithelial cells (IECs) and inflammation. Mesenchymal stem cell-deriv...
Inflammatory bowel disease (IBD) is a non-specific chronic inflammatory condition of the gastrointestinal tract, characterized by damage to intestinal epithelial cells (IECs) and inflammation. Mesenchymal stem cell-derived exosomes show therapeutic potential in IBD, but the underlying mechanisms remain unclear. This study investigates the therapeutic potential of bone marrow mesenchymal stem cell (BMSC)-derived exosomes and their molecular mechanism in IBD. We isolated and characterized exosomes from mouse BMSCs, confirming their typical size, morphology, and marker expression. In a dextran sulfate sodium (DSS)-induced mouse IBD model, administration of BMSC-derived exosomes alleviated disease severity, colon shortening, and histopathological damage. In LPS + ATP-stimulated IECs, BMSC-exos upregulated miR-148a-3p expression, enhanced cell viability, and suppressed pyroptosis-related proteins, including NOD-like receptor protein 3 (NLRP3), ASC, cleaved caspase-1, and the N-terminus of GSDMD (GSDMD-N), and inflammatory cytokines interleukin 1β (IL-1β), IL-18, tumor necrosis factor-α (TNF-α), and IL-6. Bioinformatics and dual-luciferase reporter assays identified E26 avian leukemia oncogene 1, 5' domain (Ets-1) as a direct target of miR-148a-3p. Ets-1 knockdown reversed the effects of miR-148a-3p inhibition on IEC pyroptosis and inflammation. In conclusion, BMSC-derived exosomes deliver miR-148a-3p to IECs, where it targets Ets-1 to suppress cellular pyroptosis and inflammatory responses, offering a novel therapeutic strategy for IBD.
A model of Helicobacter infection using an artificial liver constructed by a radial-flow bioreactor.
Ito K, Maehashi H, Kato T … +1 more , Matsuura T
Hum Cell · 2026 Jul · PMID 42384317 · Full text
Helicobacter DNA has been detected in liver tissues from patients with hepatocellular carcinoma and other liver diseases, suggesting a potential involvement of Helicobacter infection in hepatic pathogenesis. However, whe...
Helicobacter DNA has been detected in liver tissues from patients with hepatocellular carcinoma and other liver diseases, suggesting a potential involvement of Helicobacter infection in hepatic pathogenesis. However, whether Helicobacter pylori (H. pylori) can infect human hepatocytes and how such infection affects hepatocyte structure and function remain unclear. In this study, we used a three-dimensional (3D) bioartificial liver model reconstructed using radial-flow bioreactor technology to investigate the ability of H. pylori to infect hepatocytes and to characterize the cellular responses induced by infection. Histological analysis and electron microscopy demonstrated that H. pylori adhered to the hepatocyte surface and penetrated intercellular spaces. Infection significantly induced a threefold increase in apoptosis, accompanied by upregulation of TNF-α (1.5-fold) and activation of NF-κB (1.6-fold) (all P < 0.05). In addition, PCNA expression significantly decreased to approximately 60% of control levels (P < 0.05), whereas Akt activation was enhanced and β-catenin was predominantly localized in the cytoplasm. No significant differences were observed in Ki-67, IL-8, Ets-1, or c-Met expression compared with controls. These findings demonstrate that H. pylori can infect the 3D liver model and induce apoptosis and signaling alterations in hepatocytes, suggesting a potential pathological impact on the liver. Further studies are required to determine whether similar effects occur in the human liver in vivo.
CNOT9 affects hepatocellular carcinoma proliferation and cell cycle through the PTEN/AKT/p53 signaling pathway.
Zhang Z, Wang J, Du X … +7 more , Liu X, Liu J, Li H, Jiang Y, He K, Chen X, Han Y
Hum Cell · 2026 Jul · PMID 42384246 · Publisher ↗
Hepatocellular carcinoma (HCC) is a major health issue, but treatment options are limited. This study investigated the role of CCR4-NOT transcription complex subunit 9 (CNOT9) in the pathogenesis of HCC and its potential...
Hepatocellular carcinoma (HCC) is a major health issue, but treatment options are limited. This study investigated the role of CCR4-NOT transcription complex subunit 9 (CNOT9) in the pathogenesis of HCC and its potential as a therapeutic target. Bioinformatics analysis was performed on RNA-seq data from the TCGA and GTEx databases to assess CNOT9 expression and prognostic significance. CNOT9 expression was validated in clinical samples and cell lines using qRT-PCR and Western blot. CNOT9 was knocked down in HCC cell lines, and its effects on proliferation, apoptosis, and cell cycle were investigated using functional assays (CCK-8, EdU, colony formation, and flow cytometry). The underlying molecular mechanisms were explored via RNA-seq and Western blot analysis of the AKT pathway and cell cycle regulators. Xenograft mouse models were used to confirm the oncogenic role of CNOT9 in vivo. CNOT9 mRNA and protein expression were upregulated in HCC patients and associated with poor prognosis. CNOT9 induces abnormal proliferation of HCC cells and G2/M phase cell cycle progression. Knocking down CNOT9 reduces cell proliferation, increases apoptosis, and causes cell arrest at the G2 phase. CNOT9 knockdown activates PTEN to inhibit the AKT pathway and suppresses the expression of cell cycle-related proteins p53, p21, CCNE1 and CDK2. CNOT9-deficient tumors exhibited reduced growth in mice, supporting its pro-oncogenic role. This study first elucidates the molecular mechanism by which CNOT9 drives HCC progression through post-transcriptional regulation of the PTEN/AKT/p53 axis, providing a theoretical basis for precision treatment strategies targeting CNOT9 or the PTEN/AKT/p53 pathway.
The dynamic evolution of circulating tumor cells during glecirasib treatment predicts survival and resistance in gastrointestinal tumors with KRAS mutation.
Jiang L, Luo Y, Liang H … +11 more , Feng X, Huang Y, Li Y, Wang Z, Xu T, Zou H, Li Z, Shen L, Chen Y, Wang W, Li J
Hum Cell · 2026 Jul · PMID 42384131 · Full text
The Kirsten rat sarcoma viral oncogene homolog (KRAS) is one of the most frequently mutated oncogenes and is associated with poor prognosis. Long considered an undruggable target, KRAS has recently become actionable with...
The Kirsten rat sarcoma viral oncogene homolog (KRAS) is one of the most frequently mutated oncogenes and is associated with poor prognosis. Long considered an undruggable target, KRAS has recently become actionable with the development of direct inhibitors, particularly against the G12C mutation. Our group previously reported promising efficacy and safety results for glecirasib (JAB-21822), a novel KRAS inhibitor, in phase I/II trials involving solid tumors harboring KRAS mutations (ClinicalTrials.gov NCT05009329, NCT05194995). Nevertheless, primary (5.61%) and acquired (9.64%) resistance were observed. This study analyzed 18 patients with advanced solid tumors harboring the KRAS mutation from the JAB-21822 cohort. Longitudinal blood samples (N = 45) were collected at baseline, during partial response or stable disease, and at disease progression. Circulating tumor cells (CTCs) were isolated via a microfluidics platform (CTC100, Cellomics) and categorized into epithelial (E-CTCs), mesenchymal (M-CTCs), and epithelial/mesenchymal mixed (E/M-CTCs) subtypes. At progression, the proportion of E-CTCs showed a decreased trend, while that of E/M-CTCs increased significantly (p = 0.03). In long-term responders, the inflection points of declining M-CTC levels correlated with clinical progression and were consistent with radiographic outcomes. Baseline CTC counts > 1 were associated with shorter progression-free survival (PFS; p = 0.046). E-CTC ≤ 1 correlated with longer PFS (p = 0.025), and M-CTC ≤ 1 with longer overall survival (OS; p = 0.033). E/M-CTC ≤ 1 showed a trend toward improved OS (p = 0.086). In addition, patients with > 1 CTC who received local radiotherapy for progressive lesions after glecirasib targeted therapy had significantly prolonged PFS and OS compared to those who did not (p < 0.05).
TRERNA1-mediated acetylation represses ferroptosis of non-small cell lung cancer cells via the KAT6A/H3K23ac/TRIM24-PIK3CA pathway.
Li B, Sun Y
Hum Cell · 2026 Jun · PMID 42340519 · Publisher ↗
This study delves into the regulatory mechanism of TRERNA1 in ferroptosis of non-small cell lung cancer (NSCLC) cells. TRERNA1, KAT6A, and PIK3CA are abundantly expressed in NSCLC tissues and cells. TRERNA1 is negatively...
This study delves into the regulatory mechanism of TRERNA1 in ferroptosis of non-small cell lung cancer (NSCLC) cells. TRERNA1, KAT6A, and PIK3CA are abundantly expressed in NSCLC tissues and cells. TRERNA1 is negatively correlated with ACSL4 but positively correlated with GPX4. TRERNA1 knockdown inhibits cell proliferation and promotes ferroptosis. Mechanistically, TRERNA1 interacts with KAT6A protein to promote KAT6A expression and nuclear ectopy. KAT6A acetylates H3K23, which in turn enhances the binding of TRIM24 to H3K23ac. Therefore, TRIM24 acts as a transcriptional activator to activate the transcription of PIK3CA and inhibit ferroptosis. Overexpression of KAT6A or PIK3CA alleviateS the promoting effect of TRERNA1 knockdown on ferroptosis of NSCLC cells. In conclusion, TRERNA1 represses ferroptosis in NSCLC via the KAT6A/H3K23ac/TRIM24-PIK3CA pathway, representing a promising therapeutic strategy for NSCLC.
When fatty liver fuels kidney cancer: the THRB connection.
El-Arabey AA, Elsayed OA
Hum Cell · 2026 Jun · PMID 42337130 · Publisher ↗
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BASP1 promotes breast cancer progression and shapes an immunosuppressive microenvironment by recruiting MDSCs and suppressing T cell function.
Hu H, Feng X, Yan Z … +3 more , Qi F, Li D, Luo X
Hum Cell · 2026 Jun · PMID 42334497 · Publisher ↗
Myeloid-derived suppressor cells (MDSCs) are essential immunosuppressive elements found within the tumor microenvironment (TME) and significantly influence the development of breast cancer (BC). Given their critical role...
Myeloid-derived suppressor cells (MDSCs) are essential immunosuppressive elements found within the tumor microenvironment (TME) and significantly influence the development of breast cancer (BC). Given their critical role in cancer progression, identifying MDSC-related genes is urgently needed to develop more effective treatment strategies for BC patients. The integration of bulk RNA-seq data from the TCGA-BC cohort alongside scRNA-seq data from the GSE176078 dataset was performed for identifying MDSC-related genes through bioinformatic analysis. Subsequently, the potential of the hub gene BASP1 in predicting prognosis and immune infiltration in BC was evaluated. Furthermore, the functional role of BASP1 in BC was investigated both in vitro and in vivo. Notably, BASP1 levels were significantly higher in BC tissues than in adjacent normal tissues, and elevated BASP1 expression was closely associated with adverse clinical outcomes. Additionally, BC patients with increased BASP1 levels exhibited increased infiltration of immunosuppressive cells (M2 macrophages and Tregs) but reduced infiltration of CD8 + T cells. Functionally, downregulation of BASP1 was observed to suppress BC cell proliferation and migration in vitro through inactivation of AKT and ERK signalings. Mechanistically, BASP1 in 4T1 cells promoted MDSC migration, at least partially, via upregulating CXCL12 secretion, while BASP1 in MDSCs directly suppressed T cell function. In vivo experiments showed that BASP1 knockdown markedly inhibited tumor growth in mouse models bearing 4T1 tumors, accompanied by decreased MDSCs infiltration and increased Granzyme B + CD8 + T cell accumulation in tumor tissues. Collectively, BASP1 may serve as a potential prognostic biomarker and a therapeutic target for BC intervention, functioning both as a pro-tumorigenic gene and as an immunomodulatory molecule that shapes an immunosuppressive microenvironment.
A novel HPV E6/E7-regulated long noncoding RNA CRL suppresses cervical intraepithelial neoplasia progression by attenuating ferroptosis.
Zhang T, Yan Y, Yuan S … +2 more , Yang T, Shi C
Hum Cell · 2026 Jun · PMID 42323795 · Publisher ↗
Sustained human papillomavirus (HPV) infection induces cervical intraepithelial neoplasia (CIN), a well-established precursor lesion and risk factor for cervical cancer. However, the specific long noncoding RNAs (lncRNAs...
Sustained human papillomavirus (HPV) infection induces cervical intraepithelial neoplasia (CIN), a well-established precursor lesion and risk factor for cervical cancer. However, the specific long noncoding RNAs (lncRNAs) that regulate CIN progression remain poorly characterized. Herein, we identified a novel lncRNA, designated CIN-related lncRNA (CRL), and explored its role in CIN pathogenesis. Clinically, reduced CRL expression was significantly associated with advanced CIN stages, suggesting a potential correlation with disease severity. HPV oncoproteins E6 and E7 suppressed CRL expression through KDM2B-mediated modification of histone H3 lysine 4 trimethylation (H3K4me3). CRL repressed CIN progression and cell death in vitro. Further mechanistic investigations revealed that CRL exerted this inhibitory effect by suppressing ferroptosis. Importantly, CRL accelerated the degradation of transferrin receptor (TFRC) mRNA by interacting with the iron-sensing protein iron-responsive element-binding protein 2 (IREB2). Collectively, our findings highlight the functional importance of lncRNA CRL in HPV-induced CIN progression, specifically through its regulation of ferroptosis via the IREB2-TFRC axis. This study provides new insights into the molecular mechanisms underlying CIN development and identifies CRL as a potential candidate for CIN diagnosis or intervention.
Effects of ABCG2 dysfunction on hyperuricemia progression in premenopausal and postmenopausal women.
Miyoshi Y, Nakayama A, Nakashima H … +20 more , Hashimoto I, Kawamura Y, Shimizu S, Toyoda Y, Mizuno T, Tanabe R, Hamada Y, Nagayoshi M, Kubo Y, Okada R, Matsunaga T, Yoshioka N, Iwasawa S, Ueno M, Hayano K, Nakaoka H, Yamamoto K, Wakai K, Shinomiya N, Matsuo H
Hum Cell · 2026 Jun · PMID 42310200 · Full text
Serum uric acid (SUA) levels are influenced by environmental and genetic factors, such as sex and ABCG2 variants. Their poorlyunderstood links to menstrual status prompted us to conduct this study to evaluate the effects...
Serum uric acid (SUA) levels are influenced by environmental and genetic factors, such as sex and ABCG2 variants. Their poorlyunderstood links to menstrual status prompted us to conduct this study to evaluate the effects of menstrual status-related ABCG2 function, detectable from the presence of its dysfunctional variants, on SUA levels. Recruited for the present study were 9244 Japanese individuals, comprising 4466 women and 4778 men. We evaluated the effect size on SUA and population attributable fractions (PAFs) for hyperuricemia progression based on factors, including ABCG2 function, BMI, alcohol consumption, age, and menstrual status (in women). The results, from the viewpoint of SUA increase, showed a 25% ABCG2 dysfunction to be equivalent to the effects of a 1.67 kg/m increase in BMI, alcohol consumption of 154.2 g/week, an 18.6-year increase in age, and, in women, 42.7% due to menopause. In the tested female sample, the PAF for hyperuricemia due to ABCG2 dysfunction (32.8%) exceeded those for overweight/obesity (19.5%) and aging (28.7%). Menopausal status exhibited the highest PAF at 63.0%. In premenopausal individuals, the PAF for ABCG2 dysfunction was 45.8%, much higher than that after menopause (29.6%). Although premenopausal women generally had a lower prevalence of hyperuricemia than postmenopausal individuals, those with dysfunctional variants of ABCG2 tended to show a higher SUA increase and PAFs in premenopausal than in postmenopausal women. These results indicate that genetic testing might be helpful in preventing and treating hyperuricemia, particularly for those with higher SUA before menopause, in both individuals and in populations as a whole.
BMAL1 regulates the initial step of embryo implantation by modulating endometrial cell adhesion and migration.
Imai K, Dai Y, Ono M … +8 more , Imai Y, Kojima J, Fujiwara T, Daikoku T, Maida Y, Ando H, Fujiwara H, Nishi H
Hum Cell · 2026 Jun · PMID 42301533 · Publisher ↗
Embryo implantation is a critical and tightly regulated process essential for successful human reproduction. Although the role of endometrial receptivity is well established, the molecular mechanisms governing this proce...
Embryo implantation is a critical and tightly regulated process essential for successful human reproduction. Although the role of endometrial receptivity is well established, the molecular mechanisms governing this process are not thoroughly understood. Circadian rhythm regulators, particularly brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1 (BMAL1), have emerged as key modulators in reproductive biology. In this study, we investigated the role of BMAL1 in regulating endometrial receptivity and embryo implantation. Ishikawa cells were transfected with BMAL1-specific or control siRNA, followed by RT-qPCR, western blotting, and immunofluorescence analyses. Functional assays, including migration assays, co-culture with JEG-3 spheroids, cell viability, and cytotoxicity, were also performed. Our results demonstrated that BMAL1-knockdown in Ishikawa cells downregulated adhesion-related genes, including ITGAV, ITGB3, and ITGB5. Although total ITGB5 protein levels remained stable, its localized expression intensity was significantly reduced; the protein expression of ITGAV and ITGB3 was decreased, and cell migration was impaired. Notably, while BMAL1-knockdown compromised cellular motility, it had no significant effect on cell viability or cytotoxicity. A co-culture model with JEG-3 spheroids further demonstrated significantly decreased embryo adhesion following BMAL1-knockdown. In conclusion, BMAL1 is a critical regulator of integrin-mediated adhesion and endometrial receptivity, underscoring its potential as a therapeutic target for recurrent implantation failure.
Indole-3-acetic acid promotes differentiation while suppressing proliferation in human intestinal epithelial cells.
Mallardo M, Memon F, Pagliaro R … +2 more , Daniele A, Nigro E
Hum Cell · 2026 Jun · PMID 42283993 · Full text
Indole-3-acetic acid (IAA) is a tryptophan-derived microbial metabolite increasingly recognized for its role in intestinal homeostasis, immune regulation, and epithelial function. However, the IAA molecular effects on in...
Indole-3-acetic acid (IAA) is a tryptophan-derived microbial metabolite increasingly recognized for its role in intestinal homeostasis, immune regulation, and epithelial function. However, the IAA molecular effects on intestinal epithelial cells remain incompletely defined. Here, we investigated the effects of increasing IAA concentrations on intestinal epithelial biology using intestinal epithelial Caco-2 cell line, with a focus on cytotoxicity, epithelial repair, and differentiation. Cell viability was assessed by MTT assay; colony-forming assays were used to evaluate stemness potential; cytokine's expression was quantified by qPCR. Differentiation was analyzed through dome formation and analysis of DPPIV, SI, KLF4 and E-cadherin differentiation markers by qPCR and immunofluorescence. IAA treatment exerts concentration-dependent effects, reducing the viability and colony-forming capacity of Caco-2 cells. At higher concentrations, IAA also decreased IL-17, IL-1β, IL-6 expression. Interestingly, IAA enhanced dome formation and upregulated several differentiation markers, suggesting a shift toward a more mature epithelial phenotype. Altogether, our results indicate that IAA directly influences epithelial cell biology by modulating viability, inflammatory signaling, repair capacity, and differentiation. Our data support a potential role for this metabolite in regulating intestinal growth, repair and differentiation suggesting that IAA may contribute to intestinal homeostasis and disease pathophysiology. However, further studies are essential to understand the potential therapeutic implications related to colorectal cancer.
Immune imbalance in rheumatoid arthritis: insights from γδ T cell receptor phenotyping.
Biały S, Wielińska J, Tyczyńska KM … +2 more , Świerkot J, Bogunia-Kubik K
Hum Cell · 2026 Jun · PMID 42243586 · Full text
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and progressive joint destruction. While conventional αβ T cells have been extensively studied, the contribution...
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and progressive joint destruction. While conventional αβ T cells have been extensively studied, the contribution of γδ T cells to RA pathogenesis remains insufficiently understood. Unlike αβ T cells, γδ T cells recognize antigens independently of major histocompatibility complex (MHC) restriction, and their surface receptor expression plays a pivotal role in regulating effector functions. This study aimed to investigate the phenotype and surface receptor profile of γδ T cells in RA patients undergoing anti-TNF therapy, to better understand their potential immunoregulatory and prognostic significance. Peripheral blood samples were collected from RA patients before and during treatment with TNF inhibitors, as well as from healthy controls. Flow cytometry was used to quantify γδ T cell frequency and to assess the expression of selected activation, differentiation, and exhaustion markers on their surface. RA patients exhibited a significant reduction in the frequency of circulating γδ T cells compared with healthy controls. Moreover, γδ T cells in RA displayed phenotypic features of advanced differentiation and functional exhaustion, including altered expression of key surface receptors. The observed alterations in γδ T cell phenotype and receptor expression suggest chronic immune activation in RA. These findings highlight the potential of γδ T cell surface markers as candidate biomarkers for disease activity and response to anti-TNF therapy.
The potential of bioengineered exosomes in regenerative medicine: a next generation therapy.
Kumari S, Agnihotri A, Sharma A … +4 more , Dongre S, Tiwari A, Soni N, Bissa B
Hum Cell · 2026 Jun · PMID 42243420 · Publisher ↗
The limitations of conventional drug delivery systems and synthetic nanocarriers have spurred the search for advanced therapeutic platforms in regenerative medicine. Bioengineered exosomes/sEV, natural extracellular vesi...
The limitations of conventional drug delivery systems and synthetic nanocarriers have spurred the search for advanced therapeutic platforms in regenerative medicine. Bioengineered exosomes/sEV, natural extracellular vesicles with inherent biocompatibility and targeting capabilities, have emerged as a groundbreaking solution. This review explores the fabrication of these nanovesicles as precision drug delivery vehicles through strategies such as parent-cell modification, direct cargo loading (via sonication, electroporation, and extrusion), and surface functionalization. Critically, the synergy between exosomes and biomaterial scaffolds-including natural and synthetic polymers, hydrogels, and metallic implants-is highlighted as a transformative approach to overcome challenges of rapid clearance and off-target delivery, enabling localized, sustained release at injury sites. We detail their profound regenerative efficacy in healing chronic wounds by modulating inflammation and promoting angiogenesis, in repairing bone defects via osteogenic signaling activation, and in treating complex neurological and cardiovascular diseases by crossing biological barriers like the blood-brain barrier. Despite the promising preclinical outcomes summarized herein, significant hurdles in scalable production, standardization, and clinical translation remain. Addressing these challenges is essential to fully harness the potential of this cell-free therapy. Ultimately, bioengineered exosomes represent a versatile and powerful frontier in regenerative medicine, offering a targeted, efficient, and potentially transformative approach for tissue repair and the treatment of degenerative diseases.
Thiolutin attenuates neuroinflammation and neuronal apoptosis by suppressing microglial pyroptosis through NLRP3 inflammasome inhibition after spinal cord injury.
Zeng Y, Zhao L, Qian S
Hum Cell · 2026 Jun · PMID 42240792 · Publisher ↗
Traumatic spinal cord injury (SCI) initiates a neuroinflammatory response dominated by tissue-resident microglia. Thiolutin (THL) can weaken several inflammatory diseases by blocking the NOD-, LRR-, and pyrin domain-cont...
Traumatic spinal cord injury (SCI) initiates a neuroinflammatory response dominated by tissue-resident microglia. Thiolutin (THL) can weaken several inflammatory diseases by blocking the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation. At present, whether THL improves functional recovery after SCI is unclear. Crosstalk between neurons and microglia was simulated by a co-culture system in which microglia were activated by LPS + ATP and treated with THL. Contused SCI mouse models were constructed for studying the efficacy of THL and related mechanisms. Motor function of mice was assessed by BMS scoring, incline plane test, and footprint analysis. Pathological alterations following SCI were determined by hematoxylin-eosin, luxol fast blue, and Nissl staining. Neuronal apoptosis in vitro was assessed by flow cytometry and Tunel staining. The NLRP3 inflammasome activation, inflammatory response, and microglia polarization were assessed by western blot, ELISA, and immunofluorescence. THL treatment repressed microglia pyroptosis-induced neuronal apoptosis and inflammatory response in a co-culture system in vitro. Also, treatment with THL repressed microglial activation and M1-type polarization, along with the NLRP3 inflammasome activation. Furthermore, THL treatment improves motor function of mice with SCI, accompanied by reduced cavity area of the spinal cord, inflammatory response, M1-type microglia polarization, and enhanced remyelination and neuronal regeneration. However, THL treatment did not work in SCI-experienced Nlrp3-/- mice. THL improves motor function following SCI by repressing neuroinflammation and neuronal apoptosis via suppressing NLRP3 inflammasome-mediated microglial polarization and pyroptosis.
FUS modulates R-loops by functionally interacting with RNase H1.
Dey A, Das R, Uppal S
Hum Cell · 2026 Jun · PMID 42228326 · Publisher ↗
R-loops are three-stranded nucleic acid structures consisting of an RNA:DNA hybrid and a displaced single-stranded DNA, typically formed during transcription. Emerging evidence indicates that R-loops are not merely trans...
R-loops are three-stranded nucleic acid structures consisting of an RNA:DNA hybrid and a displaced single-stranded DNA, typically formed during transcription. Emerging evidence indicates that R-loops are not merely transcriptional byproducts, but serve as functional regulatory structures that influence chromatin organization, transcriptional pausing, and RNA processing. However, dysregulated accumulation of R-loops can induce DNA damage and genomic instability, necessitating precise mechanisms for their regulation. This study aims to elucidate the role of the RNA-binding protein FUS (Fused in Sarcoma), a protein mutated in Amyotrophic Lateral Sclerosis (ALS) and cancer, in modulating R-loop dynamics. Knockdown of FUS in HeLa cells resulted in a significant increase in global R-loop levels, as assessed by immunofluorescence and dot blot assays. Proximity ligation assay (PLA) demonstrated that FUS is in close proximity to R-loops and nascent RNA. Further, FUS was found to interact with RNase H1, a key endonuclease involved in R-loop resolution, in an R-loop dependent manner, as demonstrated by PLA and co-immunoprecipitation assay. Importantly, in vitro assays show that FUS enhances RNase H1-mediated degradation of RNA:DNA hybrids. Moreover, FUS depletion reduces RNase H1 proximity to elongating RNA polymerase II, suggesting altered engagement of RNase H1 with the transcription machinery. These findings highlight a crucial role for FUS-RNase H1 axis in regulating R-loop levels, providing insights into the potential mechanisms underlying R-loop-associated pathologies in neurodegenerative diseases linked to FUS.
Integrative analysis of lncRNAs associated with disulfidptosis-related genes for prognostic risk evaluation and tumor immune microenvironment assessment in laryngeal squamous cell carcinoma.
Liu Q, Zhang Z, Xie Y … +7 more , Tang R, Gao G, Yang Z, Liu D, Zou Y, Zhang Y, Liu M
Hum Cell · 2026 Jun · PMID 42228246 · Publisher ↗
Disulfidptosis, an emerging metabolism-associated regulated cell death pathway, involves tumor progression via the modulation of redox homeostasis. Long noncoding RNAs (lncRNAs) are promising for tumor prognostic models,...
Disulfidptosis, an emerging metabolism-associated regulated cell death pathway, involves tumor progression via the modulation of redox homeostasis. Long noncoding RNAs (lncRNAs) are promising for tumor prognostic models, but prognostic models based on lncRNAs associated with disulfidptosis-related genes remain scarce in laryngeal squamous cell carcinoma (LSCC). By utilizing TCGA-LSCC RNA sequencing datasets, this research identified differentially expressed disulfidptosis-related genes (DRGs) and lncRNAs coexpressed with these DRGs and subsequently established a 5-lncRNA prognostic signature through Pearson correlation analysis, LASSO Cox regression, and Cox regression analysis. This signature stratified LSCC patients into high-risk and low-risk subgroups with distinct survival outcomes and acceptable discriminatory performance in the analyzed TCGA-derived cohort. DUBR, a key oncogenic lncRNA in the model, correlated with poor prognosis and was functionally associated with the disulfidptosis-related gene TLN1. MeRIP-qPCR further supported that DUBR carries m6A modification, and METTL3 knockdown reduced DUBR m6A enrichment, suggesting possible METTL3-dependent m6A regulation of DUBR. DUBR silencing inhibited LSCC cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT). Moreover, transfection with a TLN1 overexpression plasmid partially restored the proliferation inhibition induced by DUBR knockdown, supporting the potential functional involvement of TLN1 in DUBR-mediated proliferative effects. Exploratory in silico drug-response analyses identified differential predicted responses to entinostat, linsitinib, and VE-822 according to risk status and DUBR expression. This internally validated signature may support exploratory prognostic risk stratification of LSCC within the analyzed TCGA-derived cohort and may highlight DUBR as a candidate molecule for further biological investigation. Further validation in independent external cohorts and dedicated disulfidptosis functional assays is required before these findings can be considered generalizable.
miR-141-5p positively regulates ACVRL1 expression to promote cervical cancer progression.
Liu J, Jiao Y, Wang J … +9 more , Cui X, Gao Y, Zhang Y, Xu J, Hao J, Hou Y, Wang W, Yang G, Li L
Hum Cell · 2026 May · PMID 42209837 · Publisher ↗
Global cancer data show a continuous rise in cervical cancer incidence and mortality, burdening public health. To effectively mitigate this challenge, elucidating molecular pathogenesis and novel drug targets are critica...
Global cancer data show a continuous rise in cervical cancer incidence and mortality, burdening public health. To effectively mitigate this challenge, elucidating molecular pathogenesis and novel drug targets are critical for advancing clinical care. In this study, abnormally expressed miRNAs in cervical cancer were identified through TCGA data analysis. Expression levels were quantified using qRT-PCR and Western Blot, at both mRNA and protein levels, respectively. miR-141-5p and ACVRL1's interaction was validated with dual-luciferase assays. Cell behavior was evaluated using assays including CCK-8 assay. In vivo tumor growth was assessed in nude mice xenograft model. Database screening and subsequent validation using cancer cell lines and clinical samples revealed aberrantly elevated expression of miR-141-5p in cervical cancer. High expression of miR-141-5p in SiHa/HeLa cells significantly promoted cellular proliferation, migration, and invasion while concurrently inhibiting apoptosis, whereas its downregulation elicited opposing effects. ACVRL1 was identified as a direct target of miR-141-5p. Overexpressing miR-141-5p markedly upregulated ACVRL1 mRNA and protein levels, while its knockdown significantly reduced ACVRL1 expression at both mRNA and protein levels. Further functional analysis showed that ACVRL1 knockdown significantly impaired cellular proliferation, migration, and invasion while enhancing apoptosis in cervical cancer cells. Rescue experiments confirmed that miR-141-5p exerted regulatory effects on these cellular behaviors, at least partially through ACVRL1. miR-141-5p downregulation significantly suppressed tumor growth in vivo, as evidenced by reduced tumor volume and weight in nude mice. In brief, this study shows that miR-141-5p upregulation in cervical cancer promotes tumor progression via ACVRL1 regulation, indicating its potential in precision oncology.
Histone H4K5 deacetylation by enhanced HDAC1 expression drives endothelial inflammation in diabetes through repression of the KLF2-eNOS axis.
Chakraborty S, Akhouri V, Katakia YT … +3 more , Ramakrishnan SK, Gaikwad AB, Majumder S
Hum Cell · 2026 May · PMID 42207449 · Publisher ↗
Endothelial dysfunction is a hallmark of diabetes, primarily driven by fluctuating blood glucose levels that contribute to vascular complications. Epigenetic regulation through histone modifications plays a crucial role...
Endothelial dysfunction is a hallmark of diabetes, primarily driven by fluctuating blood glucose levels that contribute to vascular complications. Epigenetic regulation through histone modifications plays a crucial role in mediating such pathological gene expression changes. This study delineates the differential acetylation pattern of histone H4 lysine residues in endothelial cells exposed to intermittent high glucose (IHG) conditions. IHG treatment led to a significant deacetylation of H4K5 and H4K16 residues, whereas acetylation at H4K8 and H4K12 remained unaltered. Consistently, streptozotocin (STZ)-induced diabetic rats exhibited reduced H4K5 acetylation specifically in the glomerular endothelium after six weeks of hyperglycemia. Mechanistically, human umbilical vein endothelial cells (HUVECs), human glomerular endothelial cells (HGECs) and EA.hy926 cells demonstrated a marked upregulation of histone deacetylase 1 (HDAC1) under IHG conditions, which was corroborated by elevated expression of ICAM1, p21 and reduced eNOS and KLF2. Furthermore, we also observed an increased HDAC1 expression in diabetic rat glomeruli. Among histone acetyl transferases (HATs) specific to H4K5Ac, KAT7, KAT6A, and p300 were elevated, while PCAF showed a reduction under IHG stress. Furthermore, chromatin immunoprecipitation (ChIP)-qPCR analysis revealed a loss of H4K5 acetylation enrichment on the promoters of KLF2 and eNOS under IHG. Notably, pharmacological inhibition of HDAC1 with pyroxamide or gene silencing via siRNA restored H4K5 acetylation levels. Functionally, IHG exposure suppressed endothelial nitric oxide synthase (eNOS) and its transcriptional regulator KLF2, whereas HDAC1 inhibition reinstated their expression, suggesting epigenetic restoration of endothelial homeostasis. We also observed a reversal in the ICAM1 expression upon pyroxamide treatment, which was functionally characterized by the reduced THP1 cell binding to HUVEC exposed to IHG along with pyroxamide. Collectively, our findings uncover a previously unrecognized histone H4-driven mechanism governing endothelial dysfunction in diabetes, wherein HDAC1-mediated H4K5 deacetylation represses KLF2-eNOS signaling. Targeting HDAC1 thus presents a promising therapeutic approach for mitigating vascular complications associated with diabetes.
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