IUBMB Life [JOURNAL]
Sun
200 papers
Nuclear Aggregates of Polyamines-DNA Complexes Imply a Genomic Electronic Circuit.
Iacomino G, Picariello G, D'Agostino L
IUBMB Life · 2025 Oct · PMID 41116738 · Publisher ↗
This review introduces a novel conceptual framework, which suggests that key DNA functions, including rapid gene activation, conformational changes, and chromosomal structuring, could be regulated by an electronic-like c...
This review introduces a novel conceptual framework, which suggests that key DNA functions, including rapid gene activation, conformational changes, and chromosomal structuring, could be regulated by an electronic-like circuit. The winding of strands around histones can also be attributed to an electronic effect. Many physiological processes are based on biomolecular electronic circuits and hinge on events of charge transfer. Mitochondria are recognized as the power source for cell functions, while the semiconductive properties of the nucleobases of DNA strands are controversial. Nuclear aggregates of polyamines (NAPs), supramolecular compounds formed by the interaction of polyamines (putrescine, spermidine, and spermine) with phosphate ions, are credible candidates to form hybrid structures with DNA, which support electron conduction. The final effect of their assembly is the formation of nanotubes that envelop the DNA and assist the strands in their functions. Furthermore, NAPs show the typical structure of an organic semiconductor, having an aromatic-like arrangement of their monomeric rings and a pseudo-phosphorene nanoribbon disposition of the phosphates located at their apical region. Our work should be considered innovative, since we point to these compounds as a key for a more complete understanding of cell nucleus physiology and as potential models for the development of organic electronic nanodevices.
Gastric Cancer Cell-Derived Exosomes Induce Macrophage M2 Polarization by Delivering circSMARCC1 to Promote Gastric Cancer Progression.
Zhang C, Ye J, Guan Q … +1 more , Fang X
IUBMB Life · 2025 Oct · PMID 41099193 · Publisher ↗
Exosomes, the cargo of circRNA, are crucial in cancer cell-tumor microenvironment communication. circSMARCC1 exerts a pro-tumor effect. However, this role has not been previously reported in gastric cancer (STAD). This s...
Exosomes, the cargo of circRNA, are crucial in cancer cell-tumor microenvironment communication. circSMARCC1 exerts a pro-tumor effect. However, this role has not been previously reported in gastric cancer (STAD). This study explores the role of STAD cell-derived exosomal circSMARCC1 in promoting macrophage M2 polarization. In this study, exosomes from the peripheral blood of STAD patients and AGS cells were extracted and identified. THP-1 cells were differentiated into macrophages with phorbol 12-myristate 13-acetate (PMA) and polarized to the M2 phenotype by IL-4 and IL-13. circSMARCC1 expression was analyzed in STAD tissues, cell lines, and patient-derived exosomes. The biological function of circSMARCC1 in STAD cells was evaluated by CCK-8, EdU, and Transwell assays. The role of circSMARCC1 and U2 small nuclear RNA auxiliary factor 2 (U2AF2) in regulating macrophage M2 polarization was verified by bioinformatics methods, qRT-PCR, Western blot, ELISA, and a nude mouse tumor-bearing model. Our findings demonstrated that circSMARCC1 was upregulated in STAD and associated with macrophage immune infiltration. circSMARCC1 knockdown suppressed the malignant phenotypes of STAD cells and M2 macrophage polarization, whereas its overexpression led to the contrary result. Animal experiments further confirmed circSMARCC1 regulated tumor growth and macrophage M2 polarization. Importantly, exosomal circSMARCC1 in STAD patients was increased. Knockdown of circSMARCC1 in AGS cells reduced its level in secreted exosomes and inhibited M2 polarization, whereas overexpression produced the opposite effect. Mechanistically, circSMARCC1 upregulated U2AF2 expression through exosomes to promote macrophage M2 polarization. Collectively, STAD cell-derived exosomes induced macrophage M2 polarization to promote STAD progression through circSMARCC1.
All-Trans Retinoic Acid as a Predictor and Therapeutic Agent for Vascular Calcification.
Ma J, Lu J, Lin Y … +6 more , Wu Y, Liu B, Xiang Y, Yan J, Wang Y, Meng S
IUBMB Life · 2025 Oct · PMID 41065266 · Publisher ↗
All-trans retinoic acid (ATRA), a bioactive metabolite of vitamin A, is vital for cell development and gene transcription. Coronary artery calcium (CAC) is a risk factor for cardiovascular events but lacks predictive bio...
All-trans retinoic acid (ATRA), a bioactive metabolite of vitamin A, is vital for cell development and gene transcription. Coronary artery calcium (CAC) is a risk factor for cardiovascular events but lacks predictive biomarkers and effective treatments. We investigated the correlation between serum ATRA levels and CAC scores in patients, and the potential of ATRA supplementation to alleviate vascular calcification. Proteomic analysis was conducted on rat primary vascular smooth muscle cells (VSMCs) cultured under calcifying conditions. Serum samples from 88 patients with/without CAC were analyzed for ATRA levels and CAC scores. In vivo, vascular classification was established in mice fed a high-fat and high-purine diet with vitamin D3 injection. In vitro, VSMCs were cultured with medium containing 10 mM phosphorus and 3 mM calcium with/without TGF-β (20 and 5 μg/mL) to induce calcification. Single-cell RNA sequencing was performed on mouse aortas. Proteomics showed synchronous downregulation in enzymes involved in ATRA synthesis under calcifying conditions. Serum ATRA levels were negatively correlated with CAC scores in patients. ROC curve analysis revealed an AUC of 0.9135 for ATRA (sensitivity: 73.9%, specificity: 93.3%, and optimal cutoff value: 96.64 pg/mL). In vivo, ATRA alleviated aortic calcification and downregulated RUNX2 and BMP2. In vitro, ATRA reduced calcium deposition and TNF-α and IL-6 in VSMCs. Single-cell RNA sequencing revealed that ATRA downregulated the TNF-α signaling pathways in VSMCs. Our results suggest that low serum ATRA levels may serve as an indicator of vascular calcification, and ATRA supplementation could be an effective therapy.
MyomiRs Expression in Limb Girdle Muscular Dystrophy.
Breveglieri G, Altieri MT, Rodia MT … +5 more , Costa R, Frabetti F, Cenacchi G, Sabbioni G, Borgatti M
IUBMB Life · 2025 Oct · PMID 41065084 · Full text
This manuscript is a comprehensive review focused on the role of microRNAs (miRs)-short RNA molecules-in Limb Girdle Muscular Dystrophy (LGMD). LGMD encompasses various and heterogeneous rare genetic neuromuscular diseas...
This manuscript is a comprehensive review focused on the role of microRNAs (miRs)-short RNA molecules-in Limb Girdle Muscular Dystrophy (LGMD). LGMD encompasses various and heterogeneous rare genetic neuromuscular diseases, characterized by the progressive wasting and deterioration of muscle fibers, predominantly affecting the pelvic and shoulder girdles. Similar to other muscular dystrophies, LGMD exhibits a dysregulated expression of miRs that are crucial for gene expression regulation and cellular processes. Notably, myomiRNAs, which are preferentially expressed in muscle tissue and linked to muscle cell proliferation and differentiation, appear to be particularly affected. Numerous studies have aimed to identify differentially expressed miRNAs in both physiological and pathological conditions with different purposes: (a) the identification of molecular markers for diagnostic and prognostic purposes, and for evaluation of the effects of possible therapeutic strategies; (b) the detection of a molecular signature to differentiate both LGMD from other muscular dystrophies and LGMD subtypes from each other. The main conclusions so far emerged from published studies are: (a) a high number of differentially expressed miRs have been found in both the serum and muscle fibers of LGMD patients (canonical myomiRNAs, including miR-1, miR-133a/b, and miR-206, are frequently found to be dysregulated across various LGMD subtypes); (b) circulating levels of miR-206 were found to be significantly elevated in LGMD patients compared to healthy subjects and have been suggested as a potential biomarker of general muscle damage in various muscular dystrophies; (c) possible identification of subtype-specific molecular signatures (for instance, the combination of six specific miRs has been proposed to discriminate LGMD patients from controls and to identify particular LGMD subtypes, such as LGMDR1, LGMDR2, LGMDR3, and LGMDR4); (d) currently not validated miRNA biomarkers have been described for clinical use yet in LGMD due to heterogeneity of published studies (regarding the type of biological material and techniques used) and limited number of involved patients. Therefore, while miRs show great promise for improving the molecular understanding, stratification, and management of LGMD patients, further rigorous research and validation in larger, standardized patient cohorts are necessary to confirm the clinical reliability of these identified miRNAs.
Correction to "Tissue Factor Driven Coagulation and Inflammation in Lung Injury: Insights From In Vitro and In Vivo Models".
IUBMB Life · 2025 Oct · PMID 41058094 · Publisher ↗
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LGMN as a Functionally Significant Prognostic and Immunoregulatory Biomarker in Glioma.
Nie C, Liang H, Zhou J … +5 more , Shang R, Liu H, Li K, Yu Z, Gao A
IUBMB Life · 2025 Oct · PMID 41054223 · Publisher ↗
Studies have shown that Legumain (LGMN) is a potential protease for immunosuppression in glioblastoma multiforme (GBM). Moreover, the elevated expression of LGMN in different types of cancers is linked to an unfavorable...
Studies have shown that Legumain (LGMN) is a potential protease for immunosuppression in glioblastoma multiforme (GBM). Moreover, the elevated expression of LGMN in different types of cancers is linked to an unfavorable prognosis. However, it is still not clear about the expression of LGMN in gliomas, its links with clinical situations, the ways of immune infiltration, and its significance for the prognosis. The glioma data were obtained from online databases. We verified the expression, clinical correlation, immune microenvironment, and prognostic model of LGMN by combining RNA-seq, genomic data, spatial transcriptomics (ST-seq), proteomics data, scRNA-seq data, and RT-qPCR experiments. Moreover, we explored the biological processes of LGMN through enrichment analysis and conducted immunological analysis. In comparison with normal tissues, glioma tissues show enhanced expression of LGMN both at the gene and protein levels. The experimental findings indicated that the mRNA expression of LGMN was markedly increased in U87 and U251 cells compared with those in NHA cells. Glioma patients' overall survival (OS) may be reliably predicted by the expression of LGMN. Based on a functional enrichment study, LGMN is linked to biological functions such as cell signal transduction and immunology. LGMN has a positive relationship with immune checkpoints in glioma and is additionally related to immune infiltration. scRNA-seq analysis revealed LGMN expression in cell types like Mono/Macrophages, microglia, and malignant cells. LGMN expressed in glioma is intricately linked to molecular pathology, and has significant bearings on clinical prognosis. Meanwhile, there is a connection between LGMN expression and glioma immunity. Therefore, LGMN is a novel target for independent prognosis and immunotherapy strategies in glioma.
Unravelling the Emerging Paradigms for piRNA-Target Interaction.
Das T, Ghosh B, Sarkar A … +1 more , Ghosh Z
IUBMB Life · 2025 Oct · PMID 41024727 · Publisher ↗
PIWI-interacting RNAs (piRNAs) have emerged as key gene regulators in diverse biological processes. Earlier believed to be germline-specific, these endogenous small non-coding RNAs (~26-32 nucleotides) have now been iden...
PIWI-interacting RNAs (piRNAs) have emerged as key gene regulators in diverse biological processes. Earlier believed to be germline-specific, these endogenous small non-coding RNAs (~26-32 nucleotides) have now been identified to play an active role in non-gonadal tissues as well. piRNAs in association with PIWI proteins bind to their targets and form the piRISC complex that especially regulates transposable elements (TEs) in the germline. However, after further experiments, piRNAs have been found to target and modulate the expression of non-TEs as well. Several high-throughput technologies have identified piRNA target sites in different cells and tissues of various model organisms, but all these studies have demonstrated discrete patterns of sequence complementarity between piRNA and its target. This indicates that the principle of piRNA targeting is not uniform, unlike miRNAs, due to the lack of precise knowledge regarding their targets. Further, the co-evolution of the piRNA pathway and its targeted transposons in a species-specific manner has created distinct differences in the piRNA targeting features between different species, specifically invertebrates and mammals. In this review, we focus on the current high-throughput techniques that have been used to understand the sequence-specific features that influence structural conformations favoring piRNA-target duplex formation and target cleavage. Overall, it has been observed that modulation in the degree of sequence-based complementarity between piRNA and its target sequence choreographs piRNA target interaction, which in turn enables PIWI to leverage the vast pool of piRNAs in restricting TE escape from surveillance in a sophisticated manner.
SNORA33 Promotes Clear Cell Renal Cell Carcinoma Development and Resistance to Sunitinib Through Triggering the JAK/STAT Pathway.
Sun J, Zhao S, Ren X … +9 more , Du Q, Chang Q, Guo W, Qiu L, Yang L, Zhang N, Zhao Z, Fan Y, Liu J
IUBMB Life · 2025 Sep · PMID 40990946 · Publisher ↗
Accumulating evidence has confirmed that snoRNAs exert a role in a variety of cancers; however, the role of SNORA33 in clear cell renal cell carcinoma (ccRCC) remains unclear. This study was aimed at elucidating the role...
Accumulating evidence has confirmed that snoRNAs exert a role in a variety of cancers; however, the role of SNORA33 in clear cell renal cell carcinoma (ccRCC) remains unclear. This study was aimed at elucidating the role and mechanism of SNORA33 in the tumorigenesis and progression of ccRCC. The snoRNAs expression matrices were obtained from the public TCGA and SNORic databases. Kaplan-Meier analysis was employed to investigate the survival of patients with ccRCC presenting different SNORA33 expression. The prognostic value of SNORA33 in ccRCC was examined using Cox univariate and multivariate analyses. A series of in vitro experiments were conducted to explore the functional role of SNORA33 in ccRCC. Gene set enrichment analysis (GSEA) and western blot were used to explore and validate the involved mechanisms. SNORA33 was highly expressed in patients with ccRCC and was correlated with poor prognosis. In addition, SNORA33 was intimately associated with the infiltration of diverse immune cells and positively correlated with the immune score as well as the expression levels of multiple immune checkpoint molecules, serving as a potential biomarker for immunotherapy prediction. The findings of in vitro experiments indicated that SNORA33 was capable of promoting the proliferation, invasion, migration, and resistance to sunitinib in ccRCC. SNORA33 was highly expressed in ccRCC and indicated an adverse prognosis. SNORA33 was capable of facilitating the progression, invasion, metastasis, and resistance to sunitinib of ccRCC cells through mediating the JAK/STAT pathway.
Exploring Macrophage Contribution to Vascular Calcification in Atherosclerosis.
Dabravolski SA, Popov MA, Maltseva ON … +3 more , Pavshintsev VV, Utkina AS, Orekhov AN
IUBMB Life · 2025 Sep · PMID 40990864 · Publisher ↗
Vascular calcification (VC) is a significant pathological feature of atherosclerosis, contributing to cardiovascular morbidity and mortality, particularly in populations with diabetes and chronic kidney disease (CKD). Th...
Vascular calcification (VC) is a significant pathological feature of atherosclerosis, contributing to cardiovascular morbidity and mortality, particularly in populations with diabetes and chronic kidney disease (CKD). This review examines the pivotal role of macrophages in the development and progression of VC within atherosclerotic plaques. We explore the diverse phenotypes of macrophages, particularly the pro-inflammatory M1 and anti-inflammatory M2 types, and their distinct functions in modulating vascular smooth muscle cell (VSMC) behavior. M1 macrophages promote osteogenic signaling through the secretion of pro-inflammatory cytokines and growth factors, such as oncostatin M (OSM) and bone morphogenetic proteins (BMP), which facilitate VSMC transdifferentiation and calcification. Conversely, M2 macrophages exhibit protective properties that may mitigate excessive calcification. Furthermore, we discuss the intricate balance of these macrophage populations in atherosclerotic lesions and their influence on osteoclastic differentiation, which can either enhance or inhibit the resorption of calcified deposits. Recent findings on the involvement of microRNAs (miRNAs) in regulating macrophage activation and their impact on VC highlight potential therapeutic targets for mitigating this process. By elucidating the cellular and molecular mechanisms underpinning macrophage-mediated calcification, this review aims to provide insights into the dual roles of macrophages in atherosclerosis and their significance as potential therapeutic targets. Understanding these dynamics may lead to innovative strategies for preventing VC and improving cardiovascular health outcomes, particularly in patients with diabetes and CKD.
Analysis of miRNA Expression Profiles in High Cholesterol Diet-Induced MASH Progression: Potential Effect of α-Tocopherol.
Demirel-Yalciner T, Cetinkaya B, Arga KY … +2 more , Sozen E, Ozer NK
IUBMB Life · 2025 Sep · PMID 40985305 · Publisher ↗
Metabolic dysfunction-associated fatty liver disease (MAFLD), defined by fat accumulation in more than 5% of hepatocytes, is a common metabolic syndrome worldwide. However, 30%-40% of MAFLD cases progress to metabolic dy...
Metabolic dysfunction-associated fatty liver disease (MAFLD), defined by fat accumulation in more than 5% of hepatocytes, is a common metabolic syndrome worldwide. However, 30%-40% of MAFLD cases progress to metabolic dysfunction-associated steatohepatitis (MASH), increasing the importance of the disease. MicroRNAs (miRNAs), non-coding RNA molecules approximately 21 nucleotides long, are used as biomarkers in many diseases and play a crucial role in regulating cellular processes by affecting gene expression. It is also known that miRNAs are effective in the progression of MASH and its profile depends on the stage of the disease. Therefore, we determined the relationship between MASH and miRNA profiles in an in vivo trial using an established model of cholesterol-induced MASH in rabbits. We also evaluated the impact of α-tocopherol, which is known to have a protective effect in MAFLD/MASH transition, on miRNA profiles. Regarding the limited information using rabbits, we first performed miRNA screening and identified miRNAs that are already described in rabbits or other organisms as well as the putative ones. Among those, two putative miRNAs (miR-230 and miR-1146) determined by sequencing may be important in the diagnosis and treatment of the disease. Furthermore, levels of five miRNAs (miR-122-5p, miR-199-5p, miR-145-5p, miR-27b-3p, miR-34a-5p) and their relevance in the pathogenesis of MASH were determined by RT-PCR and target gene prediction, respectively. In conclusion, the present study provides novel information regarding dysregulated miRNAs in high-cholesterol diet-induced MASH and the impact of α-tocopherol.
Tissue Factor Driven Coagulation and Inflammation in Lung Injury: Insights From In Vitro and In Vivo Models.
Varughese A, Balnadupete A, Moideen FM … +7 more , Madambath JT, Charavu R, Mugaranja K, Sunil P, Dhivya Dharsini DM, ArunBharathi A, Bhandary YP
IUBMB Life · 2025 Sep · PMID 40974114 · Publisher ↗
Lung injury and fibrosis involve a complex interplay between inflammation and coagulation, with tissue factor (TF/CF-III/Thromboplastin/CD142) acting as a crucial mediator. Despite its known role in initiating the extrin...
Lung injury and fibrosis involve a complex interplay between inflammation and coagulation, with tissue factor (TF/CF-III/Thromboplastin/CD142) acting as a crucial mediator. Despite its known role in initiating the extrinsic coagulation cascade, TF's contribution to fibrin deposition in lung injury remains underexplored. This study examines the dysregulation of the extrinsic coagulation cascade and its pathological implications in lung injury, contributing to the progression of pulmonary fibrosis (PF). Utilizing bleomycin (BLM), transforming growth factor-β (TGF-β), and TF models, we systematically investigate coagulation-driven inflammatory responses in lung pathology. By integrating in vitro (A549 and Beas2b epithelial cell models) and in vivo (C57BL/6 murine models) approaches, this study elucidates TF-mediated molecular mechanisms driving inflammation, fibrin deposition, endothelial dysfunction, and fibrotic remodeling. Protein-protein interaction (PPI) network analysis highlights functional associations between coagulation factors (CFs) and inflammatory mediators, reinforcing their involvement in lung homeostasis. Also, gene enrichment analysis identifies key biological processes, including coagulation, fibrinolysis, and immune activation, emphasizing their role in disease progression. In A549 and Beas2b epithelial cells, CF-III, CF-VII, and CF-X expression increased significantly, with A549 cells exhibiting a heightened pro-coagulant response. Elevated IL-6, TNF-α, and IL-1β levels suggest an inflammatory amplification tied to TF activation. Immunofluorescence analysis demonstrates marked TF upregulation and TNF-α activation, reinforcing the interplay between coagulation pathways and inflammatory cytokine signaling. Histological assessments (H&E, and Masson Trichrome [MT] staining) in murine lung tissues confirm fibrotic and inflammatory changes, reinforcing TF's pathogenic role. Our findings establish TF as a key molecular driver of thrombo-inflammatory lung injury, providing potential therapeutic targets to mitigate fibrosis and improve patient outcomes.
17-Oxo-DHA Potentiates Macrophage Efferocytosis via Nrf2/HO-1-Mediated Biosynthesis of Specialized Pro-Resolving Mediators.
Isot I, Demir Yangi D, Demirel-Yalciner T … +3 more , Surh YJ, Ozer NK, Sozen E
IUBMB Life · 2025 Sep · PMID 40973565 · Publisher ↗
Phagocytic engulfment of apoptotic cells, particularly neutrophils by macrophages, known as efferocytosis, is crucial in preventing secondary necrosis and promoting tissue repair. 17-Oxo-DHA, an electrophilic metabolite...
Phagocytic engulfment of apoptotic cells, particularly neutrophils by macrophages, known as efferocytosis, is crucial in preventing secondary necrosis and promoting tissue repair. 17-Oxo-DHA, an electrophilic metabolite of docosahexaenoic acid (DHA), is generated in macrophages and has been reported to contribute to inflammation resolution by enhancing efferocytosis. However, many gaps remain in our understanding of the pro-resolving effects of 17-oxo-DHA. Our results reveal that 17-oxo-DHA augments the efferocytic activity of bone marrow-derived macrophages (BMDMs) by stimulating the biosynthesis of resolvin D2 (RvD2), one of the prototypic pro-resolving mediators (SPMs), while reducing the expressions of IL-6 and TNF-α. Mechanistically, either gene silencing of Nrf2 or pharmacological inhibition of its target protein HO-1 suppresses 17-oxo-DHA-induced efferocytosis, decreasing the levels of 15-LOX, COX-2, and various SPMs. Notably, treatment of macrophages with SPMs was able to restore 17-oxo-DHA-induced efferocytosis even when HO-1 activity was suppressed. Thus, our study suggests critical roles of SPMs and the Nrf2/HO-1 axis in mediating 17-oxo-DHA-induced efferocytosis, which are novel candidate therapeutic targets in non-resolving inflammatory diseases.
DYRK1A Overexpression Drives Muscle Wasting by Impeding Myogenesis via a USP7-Axin1-β-Catenin Regulatory Axis in Mice.
Lu M, Li X, Ma L … +4 more , Wang X, Ma J, Zhao J, Lu Q
IUBMB Life · 2025 Sep · PMID 40970570 · Publisher ↗
Muscle wasting, characterized by loss of muscle mass and strength, severely impacts patient quality of life and is associated with numerous chronic diseases and aging. The molecular mechanisms are complex, involving prot...
Muscle wasting, characterized by loss of muscle mass and strength, severely impacts patient quality of life and is associated with numerous chronic diseases and aging. The molecular mechanisms are complex, involving protein synthesis/degradation imbalance. Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) and ubiquitin-specific peptidase 7 (USP7) have diverse cellular roles, but their coordinated function in skeletal muscle homeostasis remains poorly understood. DYRK1A overexpression in vivo induced muscle atrophy phenotypes, including reduced muscle mass, grip strength, fiber cross-sectional area (CSA), altered fiber type composition, and neuromuscular junction integrity, accompanied by elevated atrophy markers: muscle atrophy F-box protein (Atrogin-1), muscle ring finger 1 (MuRF-1), myostatin and suppressed myogenic markers: myoblast determination protein 1 (MyoD), myogenin (MyoG), myocyte enhancer factor 2C (Mef2c), myogenic factor 5 (Myf5). Conversely, pharmacological inhibition of DYRK1A with Harmine ameliorated these atrophy phenotypes in transgenic DYRK1A overexpressing (TgD) mice. In vivo, USP7 deficiency resulted in similar muscle wasting phenotypes. In vitro, DYRK1A overexpression or USP7 overexpression inhibited C2C12 myoblast proliferation and differentiation, effects rescued by Wnt3a treatment or USP7 knockdown, respectively. Mechanistically, DYRK1A activity suppressed active β-catenin levels. USP7 was found to interact with and deubiquitinate axis inhibition protein 1 (Axin1), leading to its stabilization. Knockdown of USP7 increased Axin1 ubiquitination and degradation, thereby promoting β-catenin signaling and myogenesis, counteracting the effects of DYRK1A. Our findings reveal a novel signaling axis where DYRK1A and USP7 cooperatively suppress Wnt/β-catenin signaling to promote muscle wasting. DYRK1A likely acts upstream, potentially phosphorylating pathway components, whereas USP7 stabilizes the β-catenin destruction complex scaffold protein Axin1 through deubiquitination. This coordinated action inhibits myogenesis and activates atrophy pathways. Targeting DYRK1A or USP7 could represent promising therapeutic strategies for muscle wasting disorders.
Pan-Cancer Analysis Identifies DIP2B as a Potential Biomarker That Inhibits Kidney Renal Clear Cell Carcinoma Progression.
Chen Y, Guo Y, Hu A … +11 more , Xu Z, Bahadar N, Xue S, Chen N, Zhang H, Song J, Li X, Jiang J, Chen R, Lu X, Chen Q
IUBMB Life · 2025 Sep · PMID 40959976 · Publisher ↗
Disco interacting protein 2 homolog B (DIP2B) is a protein-coding gene implicated in various biological processes, including embryonic development, cell cycle regulation, DNA repair, and transcriptional regulation. While...
Disco interacting protein 2 homolog B (DIP2B) is a protein-coding gene implicated in various biological processes, including embryonic development, cell cycle regulation, DNA repair, and transcriptional regulation. While its precise role in cancer remains largely unknown, emerging evidence suggests its potential involvement in tumorigenesis. In this study, we provide a comprehensive analysis of DIP2B in cancer, exploring its expression patterns, molecular functions, and potential clinical implications across different cancer types. We examined the expression, dysregulation, and prognostic significance of DIP2B. The mRNA and protein expression status of DIP2B was determined using data from TCGA, GTEx, and UALCAN. Using TCGA database data, we investigated associations between DIP2B expression and gene mutations, survival outcomes, DNA methylation, immune cell infiltration, tumor mutation burden (TMB), and drug sensitivity. High DIP2B expression was associated with poor overall survival (OS) in BRCA, KICH, LUAD, MESO, SARC, and THCA, but with improved OS in KIRC. For disease-specific survival (DSS), elevated DIP2B levels correlated with adverse outcomes in ACC, MESO, and UVM. GO and KEGG analyses implicated DIP2B in cytoskeleton organization, MAPK signaling, and ubiquitin-dependent protein catabolism. Experimental validation in KIRC cells showed that DIP2B knockdown significantly reduced cell proliferation and migration. Conversely, DIP2B exhibited oncogenic functions in LUAD cells. These findings suggest DIP2B may serve as a potential prognostic and diagnostic biomarker, displaying a unique tumor-suppressive role in KIRC progression.
Unveiling Gamma-Interferon-Inducible Lysosomal Thiol Reductase (IFI30) as a Regulator of Macrophage Polarization and Prognostic Biomarker by Multi-Transcriptome Analysis in Cervical Cancer.
Wang W, Deng Y, Feng Y … +4 more , Chen R, Xu M, Chen P, Yuan S
IUBMB Life · 2025 Sep · PMID 40937568 · Publisher ↗
Cervical cancer remains a significant challenge to global health, necessitating the development of reliable clinical prognostic models to predict patient survival outcomes with accuracy. This study aims to develop an mRN...
Cervical cancer remains a significant challenge to global health, necessitating the development of reliable clinical prognostic models to predict patient survival outcomes with accuracy. This study aims to develop an mRNA signature model based on tumor immune infiltration characteristics of cervical cancer. By employing RNA sequencing technologies at both tissue and single-cell resolutions, a survival predictive gene signature was constructed for cervical cancer through the application of machine learning methods. To further validate the key prognostic genes identified in the prognostic signature, we performed additional experiments, including tissue microarray (TMA) analysis and in vitro assays. Our developed signature model comprised nine genes, which ranks at the top tier when compared to previously published mRNA signature models. Gamma-interferon-inducible lysosomal thiol reductase (IFI30) emerged as a critical prognostic marker, validated externally through immunohistochemistry (IHC) and multiplex immunohistochemistry staining (mIHC) on cervical cancer TMAs. Notably, IFI30 exhibited pronounced expression in macrophages compared to other cell types within the tumor microenvironment (TME). We further investigated the potential role of IFI30 in regulating macrophage polarization. Specifically, a reduced expression of IFI30 in macrophages co-cultured with HeLa cells induced a polarization transition from the M2 to the M1 phenotype. In conclusion, we have successfully established a prognostic model on the basis of tumor immune infiltration characteristic of cervical cancer, highlighting IFI30 as a pivotal prognostic marker potentially involved in macrophage polarization. Future investigation is required to explore the underlying mechanisms for the advancement of therapeutic strategies in cervical cancer.
PLEKHF1 Induces Mitochondrial Dysfunction to Inhibit Osteosarcoma Growth and Metastasis.
Wan J, Cai X, Liao Z … +4 more , Liu Y, Liu Q, Zhang C, Long F
IUBMB Life · 2025 Sep · PMID 40910899 · Publisher ↗
Osteosarcoma (OS) is an uncommon malignancy with stagnant survival rates over the past four decades and early-stage metastasis, predominantly affecting children and adolescents. This study identified significant metaboli...
Osteosarcoma (OS) is an uncommon malignancy with stagnant survival rates over the past four decades and early-stage metastasis, predominantly affecting children and adolescents. This study identified significant metabolic differences between metastatic and non-metastatic OS samples through bioinformatics analysis, highlighting key processes such as cell proliferation, mitochondrial assembly, and changes in mitochondrial membrane permeability. Among differentially expressed genes, Pleckstrin Homology And FYVE Domain Containing 1 (PLEKHF1) was the most significantly downregulated in metastatic OS samples. Functional experiments demonstrated that PLEKHF1 overexpression in Saos-2 and U2OS cells induced mitochondrial dysfunction, evidenced by increased mtROS levels, decreased mitochondrial membrane potential, and altered cytochrome C distribution. Additionally, PLEKHF1 overexpression inhibited OS cell viability, colony formation, migration, invasion, and epithelial-mesenchymal transition (EMT), while promoting apoptosis. Conversely, knockdown of PLEKHF1 had the opposite effects on Saos-2 and U2OS cells. In vivo, PLEKHF1 overexpression reduced tumor growth and lung metastasis in a mouse model. Conversely, PLEKHF1 knockdown ameliorated Rotenone-induced mitochondrial dysfunction and mitophagy, partially reversing the suppressive effects of Rotenone on OS cell aggressiveness. These findings suggest that PLEKHF1 could serve as an anti-tumor factor by inducing mitochondrial dysfunction, thereby inhibiting OS growth and metastasis. The study highlights the potential of PLEKHF1 as a therapeutic target for managing osteosarcoma, providing valuable insights into the role of mitochondrial dysfunction in OS pathogenesis.
Progress in Nanocarriers-Based Approaches for the Delivery of Tyrosine Kinase Inhibitors in Bone Cancer: Trends and Prospects.
Xu D, Zhang W, Pan Y … +3 more , Wang W, Wang D, Ding J
IUBMB Life · 2025 Aug · PMID 40831326 · Publisher ↗
Bone cancer remains a life-threatening malignancy predominantly affecting pediatric and adolescent populations, with tyrosine kinase inhibitors (TKIs) emerging as promising therapeutic agents; however, their clinical uti...
Bone cancer remains a life-threatening malignancy predominantly affecting pediatric and adolescent populations, with tyrosine kinase inhibitors (TKIs) emerging as promising therapeutic agents; however, their clinical utility is limited by poor bioavailability, systemic toxicity, and inadequate tumor targeting. Recent advancements in nanocarrier-based delivery systems have significantly mitigated these limitations by enhancing targeted accumulation of TKIs at tumor sites, reducing off-target effects, and enabling controlled drug release. Various nanocarrier platforms, including liposomes, polymeric nanoparticles, micelles, dendrimers, metal- and metal oxide-based nanoparticles, carbon-based carriers, polymeric implants, and hydroxyapatite-based systems, have been systematically evaluated for their efficacy in delivering TKIs for bone cancer therapy. This review further examines the impact of nanoparticle size on cellular uptake and tumor penetration, with emphasis on liposomal and proteinaceous carriers (albumin-bound and transferrin-conjugated nanoparticles) that optimize tumor selectivity while minimizing systemic toxicity. Inorganic nanocarriers such as gold, silver, and metal oxides also demonstrate potential for multimodal therapeutic and diagnostic applications. Notwithstanding these advances, challenges including drug resistance, toxicity, and regulatory barriers remain, necessitating ongoing efforts to optimize nanocarrier formulations. This comprehensive review provides critical insights into the evolving landscape of nanotechnology-driven TKI delivery strategies aimed at enhancing therapeutic outcomes in bone cancer management.
RETRACTION: Blockade of High Mobility Group Box 1 Involved in the Protective of Curcumin on Myocardial Injury in Diabetes In Vivo and In Vitro.
IUBMB Life · 2025 Aug · PMID 40792437 · Publisher ↗
X. Yan, P. Xu, L. Zhou, J. Lu, H. Tang, Y. Zheng and H. Cao, "Blockade of High Mobility Group Box 1 Involved in the Protective of Curcumin on Myocardial Injury in Diabetes In Vivo and In Vitro," IUBMB Life 72, no. 5 (202...
X. Yan, P. Xu, L. Zhou, J. Lu, H. Tang, Y. Zheng and H. Cao, "Blockade of High Mobility Group Box 1 Involved in the Protective of Curcumin on Myocardial Injury in Diabetes In Vivo and In Vitro," IUBMB Life 72, no. 5 (2020): 931-941, https://doi.org/10.1002/iub.2226. The above article, published online on 07 January 2020 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Efstathios S. Gonos; the International Union of Biochemistry and Molecular Biology; and Wiley Periodicals LLC. The retraction has been agreed upon due to identified overlaps within the cell sections of the db/db panel in Figure 3b, as well as between the curcumin treated HMGB and PP65 panels in Figure 5b. Furthermore, elements of Figure 3b were previously published in other articles authored by different research groups. The authors did not respond to requests for comment and supporting data. As a result, the editors deem the article's results and conclusions unreliable and invalid. The authors did not respond to our notice of retraction.
ZEB1 Contributes to Drug Resistance Through Canonical Wnt Signaling in Lung Cancer.
Shi H, Wang M, Zhao Q … +1 more , Xu Y
IUBMB Life · 2025 Aug · PMID 40790986 · Publisher ↗
Lung cancer is a severe malignant disease and causes plenty of deaths each year. The survival and prognosis are disappointing for patients with recurrence or metastasis. This is partially due to the lack of mechanisms un...
Lung cancer is a severe malignant disease and causes plenty of deaths each year. The survival and prognosis are disappointing for patients with recurrence or metastasis. This is partially due to the lack of mechanisms underlying lung cancer. The ZEB1 gene was reported to promote progression in lung cancer. However, the mechanism of ZEB1 in lung cancer is a puzzle. ZEB1 and WNT7B were expressed more strongly in lung cancer cells. In clinical lung cancer tissues, ZEB1 was also overexpressed compared to the adjacent normal tissues. ZEB1 knockdown (ZEB1-KD) inhibited the activation of Wnt/β-catenin signaling. However, overexpression of WNT7B alleviated this inhibition. Furthermore, ZEB1 was shown to regulate the expression of WNT7B, and WNT7B was the bridge between ZEB1 and Wnt signaling. Cell proliferation and invasion ability were inhibited by ZEB1-KD, which was reversed by WNT7B overexpression. This regulation was supported by the expression patterns of PCNA, E-cadherin, and N-cadherin. In addition, much more cell apoptosis was induced in ZEB1-KD cells treated with Docetaxel compared to that without ZEB1-KD. This induction was reversed when WNT7B was overexpressed. Consistently, the IC50 value in the ZEB1-KD/Docetaxel group was much lower than that in the ZEB1-KD or Docetaxel alone group. In contrast, WNT7B overexpression increased the IC50 value of Docetaxel. In conclusion, ZEB1 positively regulates Wnt/β-catenin signaling in lung cancer and contributes to cancer progression. ZEB1 knockdown increases the efficacy of Docetaxel in lung cancer.
Integrated Analysis of Single-Cell and Bulk RNA Sequencing Data Reveals Cellular Senescence-Related Signatures Predicting New Potential Therapeutic Drugs in Hepatic Ischemia-Reperfusion Injury.
Chen J, Huang H, Lu Z … +2 more , Chen S, Yang C
IUBMB Life · 2025 Aug · PMID 40785649 · Publisher ↗
Three human bulk RNA sequencing (RNA-seq) datasets from the GEO database, comprising liver tissues from 76 patients with hepatic ischemia-reperfusion injury (IRI) and 80 controls, were analyzed to identify differentially...
Three human bulk RNA sequencing (RNA-seq) datasets from the GEO database, comprising liver tissues from 76 patients with hepatic ischemia-reperfusion injury (IRI) and 80 controls, were analyzed to identify differentially expressed genes related to cellular senescence (DEG-CSRGs). A total of 19 DEG-CSRGs were identified out of 866 cellular senescence-related genes, and key hub genes (e.g., JUN, FOS, ATF3) were subsequently screened. In parallel, a single-cell RNA sequencing (scRNA-seq) analysis of a mouse hepatic IRI model was conducted, profiling 4998 immune cells from control and IRI liver tissues. The analysis revealed the central roles of macrophages, monocytes, and neutrophils in the IRI process, with significant upregulation of hub gene expression in these immune cell populations. Pseudotime trajectory and intercellular communication analyses further elucidated the dynamic transitions and interactions among immune cells during IRI progression. Drug-gene interaction prediction indicated fluoxetine (FLX) as a potential therapeutic candidate, and its binding affinity to hub genes was supported by molecular docking and molecular dynamics simulations. Bioinformatics predictions were experimentally validated using in vivo mouse models (n = 5 per group) and in vitro RAW264.7 macrophage cell assays (qPCR: n = 6 per group; Western blot: n = 3 per group), confirming that FLX mitigated liver injury and suppressed the expression of cellular senescence-related factors.
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