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.

Colorectal cancer (CRC) is a prevalent and increasingly common malignancy that poses significant threats to patient survival and quality of life. This study investigates the role of ubiquitously expressed prefoldin-like chaperone (UXT) in regulating polyamine metabolism, particularly putrescine, and its impact on CRC progression. Through comprehensive bioinformatics analysis, UXT was identified as a key factor positively correlated with putrescine abundance in CRC cell lines. Clinical samples confirmed upregulation of UXT and its positive correlation with putrescine levels. Functional assays revealed that UXT knockdown reduced cell viability, migration, and invasion, while overexpression enhanced these phenotypes. Additionally, UXT knockdown decreased putrescine levels and increased the expression of ornithine decarboxylase antizymes (OAZ1, OAZ2, OAZ3), which negatively regulate polyamine synthesis. Conversely, UXT overexpression exhibited the opposite effects. In vivo experiments using a subcutaneous xenograft tumor model in nude mice showed that UXT overexpression enhanced tumor growth and putrescine levels, and UXT overexpression is associated with an increase in M2 macrophage markers, along with reduced M1-associated markers, while UXT knockdown inhibited these effects. These findings suggest that UXT contributes to CRC progression by regulating polyamine metabolism and macrophage polarization, demonstrating its potential as a therapeutic target to disrupt metabolic pathways essential for cancer cell survival and proliferation.

SIRT1 exhibited a protective role in myocardial ischemia/reperfusion injury (MI/RI), but the related mechanisms remained unclear. In this study, the regulation of SIRT1 on neddylation modification in MI/RI was explored. H9C2 cells underwent hypoxia and reoxygenation (H/R) to mimic MI/RI in vitro, and C57BL6 mice were employed to establish MI/RI model for the in vivo experiments. Mass spectrometry analysis was employed to screen the possible modified substrates of NEDD8; Western blot was performed to detect protein level; CCK8 was performed to assess cell viability; flow cytometry, TUNEL, and Cardiac Troponin T (cTNT) double staining were performed to assess cardiomyocytes apoptosis; TTC and HE staining were performed to assess infarction area and pathological changes of cardiac tissues in MI/RI mice, respectively. MLN4924 (an inhibitor of NEDD8-activating enzyme (NAE)) significantly reversed the elevated NEDD8 conjugated protein (p < 0.001) and reduced SIRT1 protein levels (p < 0.001) induced by H/R in H9C2 cells. Dead-box helicase 5 (DDX5) was screened as the possible modified substrate of NEDD8 via mass spectrometry. H/R further reduced DDX5 protein level (p < 0.001) and increased DDX5 neddylation in H9C2 cells, while which were reversed by MLN4924 or LV-SIRT1 (p < 0.05). Also, SIRT1 increased DDX5 protein level by enhancing DDX5 stability via reducing its neddylation. Functionally, hypoxia decreased cell viability (p < 0.001) and increased cell apoptosis (p < 0.001) and ROS level (p < 0.001) in H9C2 cells, whereas they were all reversed by LV-SIRT1 (p < 0.05, p < 0.001) or LV-DDX5 (p < 0.05, p < 0.001). The in vivo experiments revealed that LV-DDX5 reversed the increased infarction area (p < 0.05), necrotic myocardial fibers and cardiomyocytes apoptosis (p < 0.001) in MI/RI mice. These results suggested that SIRT1 increased DDX5 protein level to reduce cardiomyocytes apoptosis and ROS level via the inhibition of DDX5 neddylation, thus alleviating MI/RI.

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related mortality worldwide, with poor prognosis largely attributed to late-stage diagnosis and therapeutic resistance. Cisplatin (DDP) resistance is a major challenge in NSCLC treatment. Emerging evidence highlights the critical role of N6-methyladenosine (m6A) RNA modification in regulating cancer progression and drug resistance, with methyltransferase-like 3 (METTL3) serving as the key methyltransferase mediating m6A deposition on RNAs. In this study, we investigated the role of the circular RNA hsa_circ_0003176 in DDP-resistant NSCLC and its regulation by m6A modification. We found that hsa_circ_0003176 was significantly downregulated in DDP-resistant NSCLC cells and functioned as a tumor suppressor by promoting autophagy, inhibiting glycolysis, and reversing DDP resistance. Mechanistically, METTL3-mediated m6A modification suppressed hsa_circ_0003176 expression, while hsa_circ_0003176 directly targeted and destabilized ribosomal protein S6 kinase B1 (RPS6KB1) mRNA, a key regulator of mTORC1 signaling, thereby inhibiting NSCLC progression. In addition, in vivo xenograft models confirmed that hsa_circ_0003176 overexpression suppressed tumor growth and enhanced DDP sensitivity. Our study reveals the METTL3/m6A/hsa_circ_0003176/RPS6KB1 pathway as a critical pathway in NSCLC chemoresistance, offering novel therapeutic targets for overcoming DDP resistance.

Lung adenocarcinoma (LUAD), the most prevalent and aggressive form of non-small cell lung cancer. Natural compounds have gained increasing attention as potential anti-cancer agents. The therapeutic potential of chebulagic acid (CA)-a hydrolysable tannin with documented anti-proliferative properties-has not been investigated in LUAD. In the present study, functional experiments revealed that CA treatment markedly suppressed proliferation and induced mitochondrial-dependent apoptosis of LUAD cells. In addition, CA augments natural killer (NK) cell migration by enhancing LUAD CCL5 production. Quantitative proteomics identified FBXO38 as the most significantly upregulated protein following CA treatment. FBXO38 silencing abrogated CA-induced CCL5 production and NK cell migration in LUAD cells. The in vivo experiments showed that CA significantly inhibited tumor growth and enhanced NK cell infiltration in mice, accompanied by decreased Ki67+ proliferating cells, increased cleaved caspase-3+ apoptotic cells, and upregulated FBXO38 expression. Collectively, our findings demonstrate that CA may be exert anti-LUAD effects through FBXO38/CCL5-mediated NK cell recruitment.

The pathogenesis of recurrent miscarriage (RSA) is highly complex. Studies indicate that abnormal polarization of decidual macrophages is critical for pregnancy failure. The aim of this research is to investigate the function of M1 polarization of macrophages in antiphospholipid syndrome (APS)-associated RSA and the potential mechanisms involved. Macrophages from decidual tissues was assessed by flow cytometry. In vitro, THP-1 monocytes were induced by anti-β2GPI/β2GPI and M1 polarization ratio was quantified. Pro-inflammatory cytokine levels were measured by ELISA, and TLR2/MyD88/NF-κB pathway proteins were analyzed via Western blot. To examine the impact of M1 macrophages on epithelial-mesenchymal transition (EMT), migration, and invasion of trophoblasts, THP-1 and HTR-8/SVneo cells were co-cultured. The NF-κB inhibitor JSH-23 was then applied to treat THP-1 cells to assess its impact on M1 macrophage-induced trophoblast behavior. An aPL-induced abortion mice model was constructed to determine whether blocking NF-κB could inhibit decidual macrophage M1 polarization and improve pregnancy outcomes. In RSA-aPL patients, decidual M1 macrophages proportion and TLR2 expression were significantly increased, and the MyD88/NF-κB pathway was activated. Anti-β2GPI/β2GPI triggered the differentiation of THP-1 cells into M1 macrophages and activated the TLR2/MyD88/NF-κB pathway, while silencing TLR2 suppressed the M1 polarization. Furthermore, M1-polarized macrophages inhibited EMT, migration, and invasion of HTR-8/SVneo cells, which could be reversed by JSH-23. Moreover, JSH-23 reduced M1 polarization of decidual macrophages in aPL-induced abortion mice, improving pregnancy outcomes. In conclusion, this study confirms that activation of the TLR2/MyD88/NF-κB pathway promotes the M1 macrophage polarization and has a significant impact on APS-associated RSA.

Human cellular models used as materials in 183 articles published in *Human Cell* during 2025 comprise a total of 313 samples (Table1, Tables S1, S2). This highlights current trends in research involving human cells and raises concerns about the use of these materials.

Being topmost cancer in India, oral cancer management warrants discovery of novel biomarkers, treatment strategies, and targets to help with early diagnosis, treatment, and recovery. To have a continuous supply of cells, the study was aimed at generation and characterization of established cell line from buccal mucosa (BM) tumors from patients of Indian origin which can be developed as a pre-clinical tool for biomedical application. Surgically resected tumor tissue from histo-pathologically confirmed oral cancer were processed for explant culture. TBM-02 cell line was passaged and characterized for morphology and function. Further, the cell line was silenced for inflammasome pathway gene NLRP3 to evaluate its linkage with oral cancer tumorigenesis. TBM-02, successfully established from BM, was maintained up to 100 passages, exhibited epithelioid morphology, high EpCam expression and triploid ploidy with chromosomal aberrations. Novelty and human origin of TBM-02 was authenticated by Short Tandem Repeats profiling and comparison with DSMZ database. TBM-02 revealed tumorigenic potential in vitro and in vivo which was abrogated on silencing NLRP3. Increased expression of NLRP3, hallmark of chronic inflammation in TBM-02, was validated at protein and gene level and in xenograft. TBM-02 demonstrated migratory potential and was found to be a sensitive tool to study drug response. RNA sequencing demonstrated upregulation of oral cancer-associated genes and pathways. Thus, in current study, we have reported development of novel cell line from early-stage buccal mucosa cancer patient which has a strong potential to be developed and to be used as pre-clinical model for improving oral cancer management and therapeutics.Graphical Supplementary InformationThe online version contains supplementary material available at 10.1007/s13577-025-01332-6.

Pleural effusion (PE) is a common clinical manifestation associated with advanced stages of both malignant and non-malignant diseases. PE frequently occurs in advanced non-small cell lung cancer (NSCLC) and contributes to tumor progression. NSCLC accounts for more than 85% of the lung cancers and remains a problem worldwide due to its late diagnosis and low rate of response to treatment. Extracellular vesicles (EVs) present in PE are emerging as key mediators of intercellular communication, capable of transferring oncogenic signals through their molecular cargo. Among these molecules, microRNAs (miRNAs) are increasingly recognized as important drivers of cancer progression. miR-21 is a representative onco-miRNA, involved in lung cancer progression; moreover EV‐miR‐21 upregulation at the pre‐dissemination stage promotes cancer cell survival in the pleural cavity. This study compares, for the first time, the functional role of EVs isolated from malignant PE in NSCLC patients (NSCLC-PE-EVs) with those isolated from PE in patients with congestive heart failure (CHF-PE-EVs), focusing on their ability to modulate lung cancer cell behavior. The effects of these EVs were evaluated on COLO699 lung adenocarcinoma cells with proliferation, migration, and gene expression assays. NSCLC-PE was found to contain approximately twice the amount of EVs compared to CHF-PE. NSCLC-PE-EVs were enriched in the oncogenic miR-21-5p, while CHF-PE-EVs had higher levels of the tumor-suppressive miR-126-3p. Only NSCLC-PE-EVs induced dose-dependent increases in COLO699 cell proliferation and migration, consistent with elevated miR-21-5p expression. Functional studies confirmed that miR-21-5p mediates these effects by downregulating PTEN and PDCD4, and by upregulating MMP9 expression. Our findings show that NSCLC-PE-EVs promote malignant phenotypes in lung cancer cells via the transfer of miR-21-5p.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13577-025-01322-8.