Human Cell[JOURNAL]
Sun
200 papers
TPM3-NTRK1 fusion confers resistance to osimertinib in lung adenocarcinoma: a model in a continuous cell line.
Cao F, Dai J, Dong K … +6 more , Yang Z, Zhu Y, Qi C, Lin D, Bian X, Liu Y
Hum Cell · 2025 Oct · PMID 41148486 · Publisher ↗
A 62-year-old woman with EGFR exon 19-mutant lung adenocarcinoma developed resistance to osimertinib after 13 months of treatment. At progression, genetic analysis revealed persistence of the EGFR mutation and acquisitio...
A 62-year-old woman with EGFR exon 19-mutant lung adenocarcinoma developed resistance to osimertinib after 13 months of treatment. At progression, genetic analysis revealed persistence of the EGFR mutation and acquisition of a TPM3-NTRK1 fusion. Cells from the pleural effusion at this stage were cultured and established as a continuous cell line, LUNK1. LUNK1 cells displayed epithelial characteristics, with a population doubling time of 57.66 h in vitro and 100% tumorigenicity in vivo. Xenograft histopathology showed poorly differentiated lung adenocarcinoma exhibiting solid, acinar, and micropapillary patterns. Immunohistochemistry confirmed positivity for CK7, TTF-1, Napsin A, EGFR, and pan-TRK. EGFR exon 19 deletion and TPM3-NTRK1 fusion were confirmed by whole-exome and RNA sequencing, respectively, and further validated by PCR and Sanger sequencing. Drug sensitivity assays revealed an IC₅₀ of 64.0 nM for entrectinib and 806.8 nM for osimertinib, indicating reduced sensitivity to EGFR inhibition. NTRK1 knockdown significantly increased osimertinib sensitivity (124.5-264.5 fold) and reduced entrectinib sensitivity (8.7-19.0 fold), suggesting NTRK1 as a key regulator of drug response. We provided experimental evidence for that TPM3-NTRK1 fusions can mediate acquired resistance to osimertinib in a new lung adenocarcinoma cell line. LUNK1 represents a useful preclinical model for investigating resistance mechanisms and assessing dual-targeted treatment strategies.
The likely role of hydrogen sulfide-mediated regulation of pyroptosis in polycystic ovaries.
Berkel C
Hum Cell · 2025 Oct · PMID 41143939 · Publisher ↗
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Overexpression of miR-454-3p inhibits high glucose-induced ET-1 expression, leading to eNOS upregulation in endothelial cells: an integrated bioinformatics and experimental analysis.
Li W, Zhang Q, Kutryk MJB
Hum Cell · 2025 Oct · PMID 41139358 · Publisher ↗
Endothelin-1 (ET-1) plays a critical role in diabetic vasculopathy. Although clinical trials have shown promise for ET-1 receptor antagonists in treating diabetic nephropathy, their clinical use remains limited by advers...
Endothelin-1 (ET-1) plays a critical role in diabetic vasculopathy. Although clinical trials have shown promise for ET-1 receptor antagonists in treating diabetic nephropathy, their clinical use remains limited by adverse effects. MiR-454-3p targets ET-1. This study aimed to investigate the role of miR-454-3p in modulating ET-1 expression and related molecular changes in endothelial cells (ECs) under high glucose conditions using both bioinformatics and experimental approaches. Bioinformatics analysis identified 10 miR-454-3p target genes expressed in ECs previously implicated in diabetic vascular complications: ET-1, GJA1, IRF1, PIK3CB, TRPC3, SLMAP, ESR1, ITGB8, MAPK1, and PPARG. With the exception of PPARG, which protects ECs from hyperglycemia-induced damage, all have been reported to exacerbate endothelial dysfunction. Western blotting showed that high glucose increased ET-1 expression in human umbilical vein ECs (HUVECs) and human dermal microvascular endothelial cells (HDMECs), while miR-454-3p overexpression significantly suppressed this effect in both cell types. Conditioned medium (CM) from HUVECs transfected with miR-454-3p mimics enhanced eNOS expression in recipient cells, compared to control CM. Pre-treatment of HUVEC control CM with an anti-ET-1 antibody also increased eNOS expression, supporting that miR-454-3p promotes NOS production partly via ET-1 suppression. MiR-454-3p overexpression in HUVECs did not affect PPARG expression or cell proliferation. In conclusion, miR-454-3p overexpression inhibits high glucose-induced ET-1 expression in HUVECs and HDMECs, and promotes eNOS production without affecting PPARG expression in HUVECs. Our findings suggest that miR-454-3p modulates ET-1 expression under hyperglycemic conditions in vitro, which may provide a foundation for future studies exploring its potential application in managing diabetic vasculopathy.
Psoriasis and lichen planus: an immunohistochemical study of Trophoblast cell-surface antigen 2 expression in skin biopsies.
Tossetta G, Fantone S, Filosa A … +3 more , Tomasini CF, Savoia P, Marzioni D
Hum Cell · 2025 Oct · PMID 41128810 · Publisher ↗
Chronic plaque psoriasis (CPS) and lichen planus (LP) are two chronic, immune-mediated inflammatory skin conditions that often spontaneously heal, even if recurrence is common. In both diseases, the immune system mistake...
Chronic plaque psoriasis (CPS) and lichen planus (LP) are two chronic, immune-mediated inflammatory skin conditions that often spontaneously heal, even if recurrence is common. In both diseases, the immune system mistakenly targets skin cells, leading to inflammation and visible cutaneous lesions. Although the pathogenesis of LP is not fully understood, it is thought to involve an alteration of epidermal self-antigens, which activates T cells lymphocytes causing a persistent chronic inflammation at the dermal-epidermal junction. In psoriasis (PSO), an involvement of not properly considered immune cells, such as dendritic cells, monocytes, macrophages, neutrophils, keratinocytes and natural killer (NK) cells is present. Trophoblast surface antigen 2 (Trop2) is a type I transmembrane glycoprotein belonging to the epithelial cell adhesion molecule (EpCAM) family involved in cell adhesion. We conducted a retrospective study on 30 patients with the following diagnoses: 10 cases of Lichen planus (LP), 10 cases of chronic plaque psoriasis (CPS) and 10 healthy skin samples (HS). In all these samples, we performed an immunohistochemical analysis of Trop2 expression. LP and CPS samples showed a significant decrease in Trop2 expression compared to HS. Contrarily to LP, basal and supra-basal layers of CPS samples were completely negative, while the medium layers were highly positive for Trop2. The sub-corneal layers were negative for Trop2 in both LP and CPS. Our findings suggest that Trop2 may play a protective or regulatory role in maintaining skin homeostasis, particularly in the setting of immune-mediated inflammation.
Long non-coding RNA FEZF1-AS1 suppresses ferroptosis in multiple myeloma cells through KIAA1429-mediated m6A modification.
Su Q, Liu W, Wang P … +1 more , Wang M
Hum Cell · 2025 Oct · PMID 41085851 · Publisher ↗
Multiple myeloma (MM) is a hematologic malignancy characterized by abnormal clonal plasma cells in the bone marrow. This study aims to investigate the mechanism by which the long non-coding RNA FEZF1 antisense RNA 1 (FEZ...
Multiple myeloma (MM) is a hematologic malignancy characterized by abnormal clonal plasma cells in the bone marrow. This study aims to investigate the mechanism by which the long non-coding RNA FEZF1 antisense RNA 1 (FEZF1-AS1) regulates ferroptosis in MM cells through KIAA1429-mediated N6-methyladenosine (m6A) modification, and to identify novel therapeutic targets for MM therapy. The expression levels of FEZF1-AS1, Vir-like m6A methyltransferase associated protein (KIAA1429, also known as also known as VIRMA), and OTU deubiquitinase, ubiquitin aldehyde-binding 1 (OTUB1) were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis. Cellular viability, reactive oxygen species (ROS) accumulation, glutathione (GSH) levels, ferrous iron (Fe) concentration, malondialdehyde (MDA) content, and the protein levels of solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), and acyl-CoA synthetase long-chain family member 4 (ACSL4) were assessed. The interaction between FEZF1-AS1 and insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), as well as the interaction between IGF2BP3 and KIAA1429, was validated using RNA pull-down and RNA immunoprecipitation (RIP) assays. m6A and YTH N6-methyladenosine RNA-binding protein 1 (YTHDF1) on OTUB1 messenger RNA (mRNA) was analyzed. The stability of KIAA1429 mRNA and OTUB1 mRNA was also evaluated. In addition, the binding of OTUB1 to SLC7A11 and the ubiquitination status of SLC7A11 were determined by co-immunoprecipitation assays. The results showed that FEZF1-AS1, KIAA1429, and OTUB1 were highly expressed in MM cells. Knockdown of FEZF1-AS1 reduced cell viability and promoted ferroptosis. Mechanistically, FEZF1-AS1 bound to IGF2BP3, which enhanced the stability and expression of KIAA1429 mRNA. KIAA1429 facilitated m6A modification on OTUB1 mRNA, thereby promoting OTUB1 expression through YTHDF1. OTUB1 in turn stabilized SLC7A11 expression by deubiquitination. Overexpression of either KIAA1429 or OTUB1 partially reversed the pro-ferroptotic effect induced by FEZF1-AS1 inhibition in MM cells.
Cedrol impedes lung cancer metastasis by reducing tumor-associated macrophage polarization mediated by MYC-driven aerobic glycolysis.
Li Q, Liu Y, Zhang L … +3 more , Zheng Y, Feng X, Wang Y
Hum Cell · 2025 Oct · PMID 41071378 · Publisher ↗
The occurrence of tumor metastasis is associated with the phenotype of tumor-associated macrophages (TAMs). Within the tumor microenvironment, TAMs undergo metabolic reprogramming. Aerobic glycolysis contributes to TAM p...
The occurrence of tumor metastasis is associated with the phenotype of tumor-associated macrophages (TAMs). Within the tumor microenvironment, TAMs undergo metabolic reprogramming. Aerobic glycolysis contributes to TAM polarization into an M2-like phenotype. Cedrol is a component extracted from herbal medicines. Anti-cancer activities of cedrol have been reported, however, its effect on the metabolic reprogramming and pro-metastatic ability of TAMs remains unclear. Here, we found that cedrol reduced THP-1-derived macrophage polarization into M2-like phenotypes. Cedrol impaired the promoting effects of TAMs on the migration and invasion of lung cancer cells. Tumor metastasis in C57BL/6 mice was reduced following cedrol treatment, accompanied by decreases in M2-like TAMs in the lung tissues. Cedrol treatment decreased glucose consumption and lactate production and downregulated glycolysis-associated gene expression. A glycolytic inhibitor (2-DG) was utilized to confirm that suppression of glycolysis in TAMs limited the metastasis of lung cancer cells. MYC was identified as a downregulated gene in cedrol-treated TAMs based on the mRNA sequencing analysis. MYC overexpression could reverse the effects of cedrol on TAMs. Cedrol treatment reduced MYC expression at least partly via the PI3K-Akt pathway. These findings suggest that cedrol exerts anti-tumor effects by inhibiting TAM polarization into an M2-like phenotype by modulating MYC-mediated aerobic glycolysis, indicating cedrol as a potential drug for lung cancer treatment.
Multifaceted roles of microbiota-derived deoxycholic acid in gastrointestinal cancers: from barrier disruption to therapeutic implications.
Zhao H, Yang F, Yang J … +1 more , Yang S
Hum Cell · 2025 Oct · PMID 41068362 · Publisher ↗
Deoxycholic acid (DCA), a microbial-derived secondary bile acid, plays a multifunctional role in gastrointestinal (GI) carcinogenic through various molecular and cellular mechanisms. Mechanistically, DCA causes disruptio...
Deoxycholic acid (DCA), a microbial-derived secondary bile acid, plays a multifunctional role in gastrointestinal (GI) carcinogenic through various molecular and cellular mechanisms. Mechanistically, DCA causes disruption of epithelial barrier function by occludin, downregulation of claudin-5, and disruption of ERK signaling, increasing permeability and inflammation. DCA initiates DNA damage by reactive oxygen species (ROS), production of hydroxyl radicals, and degradation of p53, triggering Poly (ADP-ribose) polymerase (PARP)-mediated DNA repair signals. DCA triggers pro-oncogenic signaling such as β-catenin, M3 muscarinic receptor (M3R) transactivation of Epidermal Growth Factor Receptor (EGFR), and Nuclear factor kappa B (NF-κB), promoting cell proliferation, synthesis of Mucin 2 (MUC2), and pro-inflammatory cytokine release (e.g., Interleukin-8 (IL-8), Interferon gamma (IFN-γ)). DCA also inhibits antitumor immunity by blocking Ca⁺-Nuclear factor of activated T-cell (NFAT) 2 signaling in CD8⁺ T cells, thus disrupting cytotoxicity. DCA causes intestinal metaplasia and trans-differentiation in gastric and esophageal epithelial cells via KLF Transcription Factor 5 (KLF5)-caudal-related homeobox transcription factor 2 (CDX2) signaling. While acute levels of DCA induce apoptosis by mitochondrial membrane depolarization and caspase-9 activation, chronic accumulation leads to tumorigenesis through chronic inflammation, disruption of barrier function, and immune escape. DCA-heparin conjugates are antiangiogenic and chemo-sensitizing and offer new therapeutic windows. Taken together, these data provide evidence for the dualistic action of DCA and its central position as a microbial metabolite linking diet, barrier function, immunity, and GI carcinogenesis.
Establishment of human histiocytic sarcoma organoids dependent on the SHH/YAP pathway.
Yoshimura Y, Yoshida K, Matsuoka Y … +18 more , Sasagawa S, Nagamine N, Kukita Y, Miyamoto R, Suzuki R, Tamiya H, Kakunaga S, Yagi T, Terakawa T, Tada Y, Yokota T, Ishikawa J, Nakai S, Imura Y, Okada S, Yoshida KI, Takenaka S, Wakamatsu T
Hum Cell · 2025 Oct · PMID 41066014 · Publisher ↗
Histiocytic sarcoma is an extremely rare and aggressive malignant neoplasm characterized by immunophenotypic features of mature histiocytes. The mechanisms underlying its malignant transformation remain poorly understood...
Histiocytic sarcoma is an extremely rare and aggressive malignant neoplasm characterized by immunophenotypic features of mature histiocytes. The mechanisms underlying its malignant transformation remain poorly understood; consequently, the development of effective therapies remains limited. Resected histiocytic sarcoma specimens were cultured using a modified air-liquid interface organoid method, serially passaged, and xenografted into NOD-scid IL2Rgnull mice. Tumors formed by xenografted organoids retained histological and genetic similarities with the original tumor. Genomic analysis revealed the activation of the Sonic Hedgehog signaling pathway and amplification of Yes-associated protein 1, a key effector of the Hippo pathway. Accordingly, we evaluated the sensitivity of the organoids to the Sonic Hedgehog inhibitor vismodegib and Yes-associated protein 1 inhibitor verteporfin, both of which demonstrated potent in vitro antitumor activity in organoid cultures. This model offers a valuable preclinical platform for investigating the molecular pathology of this rare malignancy and accelerating the development of targeted therapies.
Single-cell transcriptome analysis highlights a critical role of ATG5 for endothelial cells in diabetic nephropathy.
Zhang Y, Che L, Gao H … +5 more , Zeng Q, Zhang J, Zheng Y, Li Y, Chen X
Hum Cell · 2025 Oct · PMID 41060506 · Publisher ↗
This study analyzed diabetic nephropathy (DN)-related single-cell RNA sequencing (scRNA-seq) data from public databases and dissected the mechanism by which the sirtuin 1 (SIRT1)/autophagy-related 5 (ATG5) axis mediates...
This study analyzed diabetic nephropathy (DN)-related single-cell RNA sequencing (scRNA-seq) data from public databases and dissected the mechanism by which the sirtuin 1 (SIRT1)/autophagy-related 5 (ATG5) axis mediates high glucose (HG)-induced human renal glomerular endothelial cell (HRGEC) injury. The endothelium cluster was analyzed with DN-related scRNA-seq data (GSE131882 and GSE264268). HG-induced HRGEC injury was assessed by detecting cell viability, LDH release, apoptosis, EMT, and autophagy. SRT1720 was used to activate SIRT1 in cell models and STZ-induced mouse models. Renal dysfunction and pathological injury were assessed by detecting urinary albumin, serum creatinine, and BUN levels and performing histopathological staining (H&E, PAS, Masson, and TUNEL). Analysis of the endothelium cluster discovered that the autophagy pathway in the endothelial cluster was suppressed in early-stage DN patients and mice. Moreover, HG induced cell apoptosis and EMT in HRGECs, along with elevated acetylated levels of ATG5 and decreased protein levels of ATG5. SRT1720 decreased apoptosis, EMT, and elevated autophagic flux in HG-induced HRGECs, as well as improved renal function and histopathological changes, reduced EMT, and elevated autophagy in DN mouse models. However, Atg5 silencing reversed SRT1720-mediated alterations in these parameters. The SIRT1/ATG5 axis-dependent HRGEC autophagy restoration exerts a protective effect on the kidney during DN, offering a scientific ground for developing therapeutic strategies for DN based on autophagy regulation.
Multi-omic analysis constructs ferroptosis subtypes and risk signature and reveals that PEBP1 is an important tumor suppressor in kidney cancer.
Chen S, Cheng X, Li Z … +5 more , Fan H, Xue X, Ma K, Li J, Zhu F
Hum Cell · 2025 Oct · PMID 41053452 · Publisher ↗
Ferroptosis, an iron-dependent type of regulated cell death driven by excessive lipid peroxidation, plays an important role in natural tumor suppression. In this study, we identified 23 ferroptosis-related genes associat...
Ferroptosis, an iron-dependent type of regulated cell death driven by excessive lipid peroxidation, plays an important role in natural tumor suppression. In this study, we identified 23 ferroptosis-related genes associated with prognosis in kidney cancer datasets. Based on the expression profiles of these genes, we classified kidney cancer into four distinct subtypes and constructed a 9-gene risk score to predict the prognosis of patients. Our analysis revealed that patients classified into group III and those in the low-risk group demonstrated significantly better survival probability. Moreover, the risk score exhibited strong predictive accuracy for the prognosis of kidney renal clear-cell carcinoma (KIRC) patients. Among the identified genes, PEBP1 showed elevated expression in both subtype III and the low-risk group, suggesting that it may act as a critical tumor suppressor. To further evaluate this, we examined PEBP1 expression patterns and their clinical correlations using TCGA-KIRC and KIRP cohorts. The results indicated that PEBP1 deletion was strongly associated with poor prognosis, while reduced PEBP1 expression correlated with advanced disease progression in both KIRC and KIRP patients. Functional enrichment analysis suggested that PEBP1 may be involved in pathways related to fatty acid metabolism and oxidative phosphorylation. Experimental validation supported these findings, showing that PEBP1 overexpression suppressed the proliferation and migration of kidney cancer cells. Additionally, PEBP1 promoted the accumulation of lipid reactive oxygen species (ROS), an effect that was reversed by a ferroptosis inhibitor. Conversely, silencing PEBP1 counteracted the lipid ROS induced by RSL4, a ferroptosis activator. In summary, our results demonstrate that PEBP1 functions as a potential tumor suppressor in kidney cancer and may serve as a promising prognostic biomarker and therapeutic target.
Emerging role of the E3 ubiquitin ligase RNF114 in health and disease.
Wang Q, Cao S, Sun Z … +2 more , Jia Z, Yang S
Hum Cell · 2025 Oct · PMID 41046487 · Publisher ↗
Ubiquitination plays important roles in various biological processes and diseases by affecting the subcellular localization, function, and degradation of substrates. Multiple ubiquitin-associated enzymes jointly mediate...
Ubiquitination plays important roles in various biological processes and diseases by affecting the subcellular localization, function, and degradation of substrates. Multiple ubiquitin-associated enzymes jointly mediate the binding of ubiquitin to substrates. Over the past few decades, numerous E3 ubiquitin ligases, including RING finger protein 114 (RNF114), have been well studied. Research has revealed the involvement of RNF114 in various biological processes, including embryonic development, the cell cycle, genome stability, the immune response, and osteoclastogenesis. Additionally, RNF114 is implicated in multiple diseases, such as viral infections, psoriasis, liver fibrosis, and cancer. This review recapitulates the most recent advances regarding RNF114 and provides possible directions for future research.
Elucidating the risk factors and oncogene drivers of acute myeloid leukemia.
Sanya DRA, Onésime D
Hum Cell · 2025 Oct · PMID 41046303 · Publisher ↗
The hematopoietic system is critical for maintaining physiological homeostasis but is also implicated in various pathologies. The magnitude of hematopoietic responses to perturbations or diseases exhibits significant int...
The hematopoietic system is critical for maintaining physiological homeostasis but is also implicated in various pathologies. The magnitude of hematopoietic responses to perturbations or diseases exhibits significant inter-individual variability, underscoring the need to identify predictors and determinants of blood responsiveness in humans. These reactions are shaped not only by genetic factors but also by epigenetic modifications and environmental effects. Elucidating baseline predictors of hematopoietic responses and their molecular underpinnings is of particular interest in acute myeloid leukemia (AML), given their potential to inform malignancy immunotherapy. Due to limited understanding of the cellular and molecular mechanisms driving diverse AML subtypes in pediatric and adult patients, coupled with an increasing prevalence of refractory or relapsed hematological malignancies, this review highlights underexplored prognostic biomarkers, their molecular mechanisms, and their potential clinical utility in optimizing therapeutic strategies for improved patient survival. It examines recent advances in AML research and vaccine development, focusing on efforts to address highly aggressive and rare AML subtypes driven by aberrantly activated transcription factors. The review also addresses clinical implications for overall survival and treatment response, as well as promising vaccine candidates. Additionally, it highlights newly identified mutations and high-risk molecular markers that could enhance risk stratification for early disease progression, identifying patients who may benefit from allogeneic stem cell transplantation or enrollment in clinical trials.
ZWINT down-regulated by miR-495-3p inhibited lung metastasis of breast cancer by blocking p38 MAPK signaling pathway activation.
Shao MT, Li WW, Li Y … +7 more , Chen P, Yu SS, Lu WJ, Chen CM, Dong Y, Zhang YW, Zhang QC
Hum Cell · 2025 Oct · PMID 41046283 · Full text
Breast cancer metastasis is the primary cause of patient mortality, yet effective therapeutic targets remain limited. Building on our prior identification of ZWINT as a prognostic marker linked to metastasis, this study...
Breast cancer metastasis is the primary cause of patient mortality, yet effective therapeutic targets remain limited. Building on our prior identification of ZWINT as a prognostic marker linked to metastasis, this study defines its critical functional role and regulatory mechanism. Multi-omics analysis revealed a strong association between ZWINT expression and metastatic processes across breast cancer subtypes. Functionally, ZWINT knockdown significantly inhibited breast cancer cell migration and invasion in vitro and dramatically reduced lung metastasis in vivo. Mechanistically, we discovered that miR-495-3p directly targets and suppresses ZWINT expression, and this miR-495-3p/ZWINT axis acts through inhibiting p38 MAPK pathway activation to suppress metastatic progression in vitro. Our findings demonstrate that ZWINT drives breast cancer metastasis and is negatively regulated by miR-495-3p. The newly identified miR-495-3p/ZWINT/p38 MAPK axis may provide a promising therapeutic target for suppressing breast cancer progression.
Podocytes in health and disease: from development to regeneration.
Nishimura Y
Hum Cell · 2025 Oct · PMID 41037130 · Publisher ↗
Podocytes are highly specialized epithelial cells that are essential for maintaining the glomerular filtration barrier. They originate from the metanephric mesenchyme during kidney development, with differentiation tight...
Podocytes are highly specialized epithelial cells that are essential for maintaining the glomerular filtration barrier. They originate from the metanephric mesenchyme during kidney development, with differentiation tightly regulated by transcription factors, such as Wt1, MafB, and Lmx1b, as well as signaling pathways, including Wnt and Notch. Mature podocytes form intricate foot processes and slit diaphragms, coordinating membrane proteins, such as nephrin and podocin, with the actin cytoskeleton to ensure selective filtration. Owing to their limited regenerative capacity, podocyte injury caused by genetic mutations, mechanical stress, metabolic disorders, or inflammation leads to proteinuria, glomerulosclerosis, and the progression of chronic kidney disease. Recent studies have elucidated diverse injury mechanisms, including apoptosis, necroptosis, ferroptosis, and cytoskeletal dysregulation, highlighting aging and lipid metabolism as key modulators of podocyte vulnerability. Advances in stem cell technology and kidney organoids have enabled the modeling of podocyte development and disease, paving the way for regenerative strategies. This review provides a comprehensive overview of podocyte biology, injury mechanisms, and emerging therapeutic approaches, emphasizing translational opportunities for protecting and restoring podocyte function in kidney diseases.
METTL14 knockdown augmented the polarization of M2-like macrophages to promote acute myeloid leukemia progression.
Wang M, Xie Z, Tan Y … +4 more , Zhou Y, Wang S, Zhang P, Li J
Hum Cell · 2025 Sep · PMID 41026373 · Publisher ↗
Within the m6A methyltransferase complex, methyltransferase-like 14 (METTL14) constitutes a pivotal component. This study aims to elucidate the role of METTL14 in macrophage differentiation and its involvement in the pro...
Within the m6A methyltransferase complex, methyltransferase-like 14 (METTL14) constitutes a pivotal component. This study aims to elucidate the role of METTL14 in macrophage differentiation and its involvement in the progression of acute myeloid leukemia (AML) through the modulation of programmed cell death-ligand 1 (PD-L1) expression in M2-like macrophages. The expression levels of METTL14 in M1-like and M2-like macrophages were quantified using real-time quantitative polymerase chain reaction (QRT-PCR). Macrophage differentiation in THP-1 cells was induced via treatment with phorbol 12-myristate 13-acetate (PMA), followed by lentiviral-mediated overexpression or knockdown of METTL14. Changes in the expression of CD86, iNOS, Arg-1, and CD206 were evaluated. The effects of METTL14 knockdown and overexpression on macrophage differentiation, M2 macrophage proliferation, and apoptosis was assessed. AML cells were co-cultured with M2 macrophages subjected to either METTL14 knockdown or overexpression, and subsequent changes in AML cell proliferation, apoptosis, migration, invasion, and m6A methylation levels were investigated. The expression of METTL14 mRNA was elevated in M1-like macrophages. Knockdown of METTL14 resulted in a significantly reduction in the expression of M1 markers, such as CD86 and iNOS, while concurrently increasing the expression of M2 markers, including Arg-1 and CD206. Additionally, the depletion of METTL14 facilitated the proliferation of M2-like macrophages, inhibited apoptosis, and decreased phagocytic capacity. Conversely, overexpression of METTL14 yielded opposite outcomes. Co-culture experiments demonstrated that M2-like macrophages with METTL14 knockdown significantly promoted the proliferation of AML cell, suppressed apoptosis, and enhanced migration and invasion. Concurrently, cellular m6A levels were elevated. Treatment with anti-PD-L1 partially reversed the effects of METTL14 knockdown. These findings suggest that METTL14 may enhance the proliferation of AML cells while inhibiting apoptosis by influencing macrophage differentiation and modulating macrophage function, with these effects being associated with YTHDF1 and PD-L1.
Eucommia ulmoides (Duzhong) extract alleviates cerebral stroke by inhibiting ferroptosis-related gene DNA Damage-Inducible Transcript 4 (DDIT4) expression.
Qi X, Deng M, Li M … +2 more , Ma W, Zhou Y
Hum Cell · 2025 Sep · PMID 41023460 · Publisher ↗
Cerebral stroke is an acute cerebrovascular disease, which is characterized by significant morbidity, death, and disability rate. Ischemic stroke is more than hemorrhagic stroke and accounts for 60-70% of all strokes. Th...
Cerebral stroke is an acute cerebrovascular disease, which is characterized by significant morbidity, death, and disability rate. Ischemic stroke is more than hemorrhagic stroke and accounts for 60-70% of all strokes. The present study explored the mechanisms of Eucommia ulmoides extract (EUE) in the treatment of ischemic stroke. Middle cerebral artery occlusion (MCAO) mouse models and oxygen and glucose deprivation (OGD) SH-SY5Y cell models were constructed to mimic ischemic stroke, and mice and cells were treated with gradient concentrations of EUE. The neurological function and brain tissue damage in mice were assessed using multiple parameters. Then the iron contents in cerebral tissue samples and neuronal cells were examined, and the expression levels of reactive oxygen species-related indicators and iron metabolism-related proteins were detected. EUE alleviated the ferroptosis process within cerebral tissue samples of MCAO mice and OGD-triggered neuronal cells, thereby mitigating neurological function and brain tissue damage by activating PI3K/Akt pathway. The target drug genes of EUE were searched by network pharmacology and molecular docking and found that the ferroptosis-related gene DDIT4 is the potential EUE-targeted gene in the therapy of ischemic stroke. DDIT4 expression was upregulated within cerebral brain samples of MCAO mice and OGD-triggered neuronal cells, and EUE could inhibit DDIT4 expression. The protective effect of EUE on neuronal cells could be partially reversed by overexpression of DDIT4. Moreover, EUE alleviated ferroptosis and improved neurological function in MCAO mice by suppressing DDIT4 expression and modulating the PI3K/Akt pathway. In conclusion, EUE exerts its neuroprotective effect against cerebral stroke by inhibiting DDIT4 expression and ferroptosis by regulating the PI3K/Akt pathway, and DDIT4 has been predicted to be an underlying therapeutic target for the treatment of ischemic stroke.
Hofbauer cell alterations and potential role in the pathophysiology of HELLP syndrome.
Ezaki A, Sagara A, Komohara Y … +14 more , Pan C, Yano H, Zhao S, Yamamoto M, Imamura A, Akita H, Su J, Shirotani R, Takahashi T, Yoshii D, Fujiwara Y, Yamamoto M, Yamaguchi M, Kondoh E
Hum Cell · 2025 Sep · PMID 41023243 · Publisher ↗
HELLP syndrome, a severe pregnancy complication characterized by hemolysis, elevated liver enzymes, and low platelet count, is a subtype of preeclampsia (PE). However, its rapid onset and unique clinical features suggest...
HELLP syndrome, a severe pregnancy complication characterized by hemolysis, elevated liver enzymes, and low platelet count, is a subtype of preeclampsia (PE). However, its rapid onset and unique clinical features suggest distinct underlying mechanisms. Although Hofbauer cells are essential for maintaining immune homeostasis, their involvement in HELLP syndrome remains unclear. We conducted transcriptomic analysis of public data sets to assess macrophage-associated gene expression in placentas from control, PE, and HELLP cases. Immunohistochemistry and image analysis were performed on formalin-fixed paraffin-embedded placental tissues to quantify macrophage density and size, and electron microscopy was conducted to evaluate ultrastructural features. Gene expression analysis revealed a significant reduction in AIF1 (Iba1) and CD163 expression in PE placentas, while CD163 expression was relatively preserved in HELLP. Immunohistochemistry confirmed decreased Hofbauer cell density in PE placentas, whereas enlarged Hofbauer cells with increased rough endoplasmic reticulum, suggesting enhanced activation status, were seen in HELLP. Hofbauer cells exhibit distinct morphological and molecular changes in HELLP syndrome compared with PE, which implicates their potential involvement in the pathophysiology of HELLP. These findings provide new insights into the fetal immune environment in pregnancy-related hypertensive disorders.
Exportin-1 and epigenetic modifications interaction: more than nuclear transport.
Benetatos L, Hatzimichael E, Kapsali E
Hum Cell · 2025 Sep · PMID 40991079 · Publisher ↗
Exportin-1 (XPO1) is fundamental in the regulation of nuclear-to-cytoplasm transportation. XPO1 has the ability to transport hundreds of proteins and several different types of mRNAs responsible for proper cellular biolo...
Exportin-1 (XPO1) is fundamental in the regulation of nuclear-to-cytoplasm transportation. XPO1 has the ability to transport hundreds of proteins and several different types of mRNAs responsible for proper cellular biology. Deregulation of the XPO1 transportation system aberrantly translocates transcription factors promoting the pathogenesis of diseases including cancer. However, XPO1 has transport-independent functions that involve epigenetic modifications. XPO1 associates with chromatin, recruiting oncogenic fusion proteins to target genes affecting chromatin structure and function. That intriguing association also affects transcriptional activation resulting in oncogenesis. XPO1 also regulates other epigenetic pathways and is epigenetically regulated as well. Herein, we report most recent findings on that topic, and we discuss the mechanisms and the consequences of normal and aberrant XPO1 association with the epigenetic marks.
Generation of human induced pluripotent stem cell lines derived from Wolf-Hirschhorn syndrome patients with chromosomal 4p deletion.
Shimizu T, Takami M, Matsuo-Takasaki M … +4 more , Noguchi M, Nakamura Y, Hayata T, Hayashi Y
Hum Cell · 2025 Sep · PMID 40971060 · Full text
Wolf-Hirschhorn syndrome (WHS) is a devastating congenital disease caused by deletions on the short arm of chromosome 4 (4p), for which no curative treatments currently exist. To facilitate the development of therapeutic...
Wolf-Hirschhorn syndrome (WHS) is a devastating congenital disease caused by deletions on the short arm of chromosome 4 (4p), for which no curative treatments currently exist. To facilitate the development of therapeutic strategies, the development of experimental models of WHS is crucial for investigating its etiology and pathogenesis, which remain elusive. In this study, we successfully generated human induced pluripotent stem cells (hiPSCs) from three fibroblast lines from WHS patients. We then characterized these hiPSCs, along with one hiPSC line previously generated from peripheral blood mononuclear cells, as part of a Japanese nationwide project. All four hiPSC lines exhibited characteristics of self-renewal, pluripotency, and karyotypes with expected 4p deletions. Copy number variation microarray analysis revealed that these WHS-specific hiPSCs carried hemizygous deletions in p15.1-p16.3 regions, commonly encompassing 100 genes. Transcriptome analysis showed that the expression of these genes faithfully reflected hemizygous deletion in these WHS-specific hiPSCs and that these down-regulated genes were associated with the development of neural crest cells. These results indicate that WHS-specific hiPSCs can recapitulate the abnormal genomic structure genes related to and the gene expression profile observed in WHS patients. Given the limited understanding of the molecular pathogenesis of WHS, these cellular resources will be instrumental in modeling disease phenotypes and in advancing novel therapies for this syndrome.
ODC1 loss upon KLF6 upregulation promotes macrophage pyroptosis and acute kidney injury in sepsis.
Ding J, Zhang S, Zhang X
Hum Cell · 2025 Sep · PMID 40962975 · Publisher ↗
The excessive inflammatory cascade in sepsis represents a major cause of multiorgan injuries, including sepsis-associated acute kidney injury (SAKI). Following the bioinformatics prediction, this study aims to investigat...
The excessive inflammatory cascade in sepsis represents a major cause of multiorgan injuries, including sepsis-associated acute kidney injury (SAKI). Following the bioinformatics prediction, this study aims to investigate the role of ornithine decarboxylase 1 (ODC1) in macrophage phenotype in SAKI. C57BL/6 J mice and mouse bone marrow-derived macrophages or THP-1 cells were subjected to lipopolysaccharide (LPS) treatments to generate septic models. RT-qPCR and western blot assays revealed a reduced expression pattern of ODC1 in the kidney of mice and the BMDMs following LPS challenges. Upregulation of ODC1 ameliorated kidney injury, reduced M1 polarization of macrophages, and alleviated inflammatory cytokine secretion. Moreover, this upregulation inactivated the nuclear factor-kappa B signaling and enhanced macrophage autophagy while reducing pyroptosis. KLF6, highly expressed in septic mice, was found to repress ODC1 transcription by binding to its promoter. Silencing of KLF6 similarly promoted macrophage autophagy and inhibited pyroptosis, ameliorating kidney injury and inflammation in mice. These effects were, however, negated by the additional ODC1 silencing. Collectively, this study suggests that KLF6-mediated ODC1 loss inhibits macrophage autophagy while promoting pyroptosis, thus resulting in inflammation and progression of SAKI.
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