IUBMB Life [JOURNAL]
Sun
200 papers
Bioinformatics-Based Exploration of LMO4-Regulated Hippo Pathway to Reverse Adriamycin Resistance in Breast Cancer.
Wu Y, Gao J, Su Z … +6 more , Gao A, Zhao J, Qiao G, Ye M, Liu D, Xu J
IUBMB Life · 2025 Aug · PMID 40785591 · Publisher ↗
The development of acquired drug resistance in breast cancer (BC) significantly compromises treatment efficacy and patient survival, yet the underlying molecular mechanisms remain completely understood. In this study, we...
The development of acquired drug resistance in breast cancer (BC) significantly compromises treatment efficacy and patient survival, yet the underlying molecular mechanisms remain completely understood. In this study, we investigated the role of the Hippo signaling pathway and its regulatory factor, LIM Domain Only 4 (LMO4), in the acquired Adriamycin (ADR)-resistant MCF-7 (AdrR) cells. Using a combination of bioinformatics and experimental approaches, we demonstrated that AdrR cells exhibit defective apoptosis upon ADR treatment, characterized by abnormal expression of apoptotic proteins such as BAX and BCL2. RNA sequencing (RNA-seq) and ATAC sequencing (ATAC-seq) revealed significant dysregulation of the Hippo pathway in AdrR cells compared to parental MCF-7 cells, suggesting its involvement in mediating drug resistance. Further experiments showed that small interfering RNA (siRNA)-mediated knockdown of LMO4 (siLMO4) altered the expression of apoptotic proteins and partially restored ADR sensitivity in AdrR cells. Mechanistically, LMO4 was found to modulate the Hippo pathway, as evidenced by changes in the nuclear translocation of YAP and the phosphorylation levels of key Hippo pathway components (MST1/2 and YAP). Inhibition of the Hippo pathway using a Lats kinase inhibitor further confirmed its role in regulating drug resistance. Our findings highlight the critical involvement of the LMO4-Hippo signaling axis in ADR resistance and propose LMO4 as a potential therapeutic target for reversing chemoresistance in BC. This study provides novel insights into the molecular mechanisms of drug resistance and offers a foundation for future research aimed at improving treatment strategies for ADR-resistant breast cancer.
CircZNF418 Prevents Intervertebral Disc Degeneration by Targeting the HuR/SIRT6 Axis to Protect Against Oxidative Stress-Induced Ferroptosis and Senescence.
Wei K, Feng D, Fan D … +5 more , Chen J, Du Q, Xue J, Zhong G, Chen J
IUBMB Life · 2025 Aug · PMID 40767364 · Publisher ↗
Intervertebral disc degeneration (IVDD) is a common degenerative disorder affecting the spine. Ferroptosis and cellular senescence are key pathological features driving IVDD progression, but the mechanisms involved in th...
Intervertebral disc degeneration (IVDD) is a common degenerative disorder affecting the spine. Ferroptosis and cellular senescence are key pathological features driving IVDD progression, but the mechanisms involved in their regulation remain incompletely understood. While circular RNAs (circRNAs) have been implicated in nucleus pulposus cells (NPCs) function, the specific role of circZNF418 in IVDD has not been explored. In this study, we aimed to investigate the function and mechanism of circZNF418 in IVDD, focusing on its impact on oxidative stress-induced ferroptosis and senescence in NPCs. NPCs were treated with tert-butyl hydroperoxide to mimic oxidative stress during IVDD progression. The levels of malondialdehyde (MDA) and glutathione (GSH) were quantified using commercial kits, and senescence was assessed using SA-β-gal staining. Gene and protein expression was analyzed using qPCR, Western blotting, immunofluorescence, and immunohistochemistry. RNA pull-down and immunoprecipitation were used to examine interactions among circZNF418, HuR, and SIRT6. circZNF418 levels were found to be lower in degenerative nucleus pulposus tissues, associated with increased ferroptosis and cellular senescence. circZNF418 expression declined in response to oxidative stress and was correlated with increased NPC senescence and ferroptosis. Overexpression of circZNF418 protected NPCs from oxidative damage, while its knockdown exacerbated senescence and ferroptosis. Silencing of SIRT6 partially reversed the protective effects of circZNF418 overexpression. Additionally, both circZNF418 and SIRT6 were shown to bind to HuR, with circZNF418 promoting SIRT6 expression, which was reversed by HuR silencing. The findings indicate that circZNF418 regulates NPC senescence and ferroptosis by upregulating SIRT6. A novel signaling pathway, the novel circZNF418/HuR/SIRT6 axis, was identified, showing its potential in IVDD therapy, while circZNF418 was identified as a potential target, thus providing new diagnostic biomarkers and the development of effective treatments for IVDD.
Cannabidiol Suppresses EMT in Pancreatic Cancer via Inhibition of MALAT1 lncRNA and PI3K/Akt/mTOR Signaling Pathway.
Kim NY, Jung YY, Um JY … +1 more , Ahn KS
IUBMB Life · 2025 Aug · PMID 40767250 · Full text
Pancreatic ductal adenocarcinoma (PDAC) is characterized by aggressive metastasis and poor response to chemotherapy, largely driven by epithelial-mesenchymal transition (EMT) and chemokine signaling. Cannabidiol (CBD), a...
Pancreatic ductal adenocarcinoma (PDAC) is characterized by aggressive metastasis and poor response to chemotherapy, largely driven by epithelial-mesenchymal transition (EMT) and chemokine signaling. Cannabidiol (CBD), a non-psychoactive phytocannabinoid, has shown anticancer potential, yet its mechanisms in EMT regulation remain underexplored in PDAC. In this study, we demonstrate that CBD significantly suppresses the expression of CXCR4/CXCR7 and matrix metalloproteinases (MMP-2/9), leading to reduced migration and invasion of MIA PaCa-2, PANC-1, and AsPC-1 cells. Moreover, CBD reversed CXCL12-induced EMT by downregulating mesenchymal markers and restoring epithelial markers. Mechanistically, CBD inhibited the expression of the long non-coding RNA MALAT1, a known EMT regulator, and antagonized its pro-invasive effects. Overexpression of MALAT1 activated the PI3K/Akt/mTOR pathway and enhanced EMT-related protein expression, all of which were effectively reversed by CBD. Furthermore, the combination of CBD and gemcitabine exhibited synergistic inhibition of MALAT1, EMT markers, and PI3K/Akt/mTOR signaling without inducing cytotoxicity, suggesting a therapeutic advantage. Collectively, these findings reveal a novel mechanism through which CBD impedes PDAC metastasis and underscore its promise as a complementary agent in chemotherapy regimens.
RING Finger Protein 4 (RNF4) Reduces Nonalcoholic Fatty Liver Disease Accumulation by Promoting the SUMOylation of HIF-2α and Regulating the PPARα Signaling Pathway.
Yang L, Ni Q, He Y … +10 more , Liu S, Gan L, Dai A, Hu Y, Liu Q, Yang X, Li J, Tao Y, Li Y, Xu M
IUBMB Life · 2025 Aug · PMID 40739771 · Publisher ↗
RING finger protein 4 (RNF4) acts as a SUMO-targeted ubiquitin ligase, principally regulating protein stability and playing a crucial role in liver injury, inflammatory, and cholestatic diseases. In spite of this, it is...
RING finger protein 4 (RNF4) acts as a SUMO-targeted ubiquitin ligase, principally regulating protein stability and playing a crucial role in liver injury, inflammatory, and cholestatic diseases. In spite of this, it is unclear how it contributes to nonalcoholic fatty liver disease (NAFLD). The rat model of NAFLD was constructed by feeding a high-fat diet (HFD), and HepG2 cells were treated with 1 mmol/L oleic acid (OA) for 24 h. Real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting were used to measure the expression of associated genes and proteins. Oil red O staining, enzyme-linked immunosorbent assay (ELISA), flow cytometry, and hematoxylin-eosin (HE) staining were used to assess damage to HepG2 cells and rat liver tissues. RNF4 expression is reduced in NAFLD. Overexpression of RNF4 in HepG2 cells reduced triglyceride (TG) and total cholesterol (TC) levels and increased high density lipoprotein cholesterol (HDL-C) levels. In addition, overexpression of RNF4 suppressed lipogenic genes liver X receptor alpha (LXRα), fatty acid synthase (FAS), stearoyl-CoA desaturase-1 (SCD1), and cytochrome P4A11 (Cyp4a11), inflammatory cytokines tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), and interleukin-6 (IL-6), and cell apoptosis; it also inhibited lipid accumulation in vivo and improved liver tissue pathology, thereby mitigating NAFLD progression. Mechanistically, RNF4 promotes SUMOylation and ubiquitin-mediated degradation of hypoxia inducible factor-2 alpha (HIF-2α), thereby enhancing peroxisome proliferator-activated receptor alpha (PPARα) expression, reducing lipid accumulation, inflammation, and cell apoptosis, ultimately alleviating NAFLD development. Our research indicates that RNF4 may be a novel therapeutic target for NAFLD.
The Synergic Inhibition of Wilforlide A With Cisplatin in Lung Cancer Is Mediated Through Caspase-3 and NFκB Signaling.
Peng Z, Xiao X, Lu X … +4 more , Cao D, Fang H, Yang Z, He D
IUBMB Life · 2025 Aug · PMID 40739765 · Publisher ↗
Lung cancer is a malignant disease in the respiratory system and accounts for hundreds of thousands of deaths each year. Cisplatin is the first-line drug in the clinic for lung cancer. However, drug resistance and side e...
Lung cancer is a malignant disease in the respiratory system and accounts for hundreds of thousands of deaths each year. Cisplatin is the first-line drug in the clinic for lung cancer. However, drug resistance and side effects are becoming a big problem. Combination therapy is a good strategy to deal with this issue and has exhibited better efficacy. Wilforlide A (WA), a natural herb extract, has anti-inflammatory activity and increases the efficacy of docetaxel in prostate cancer. Accordingly, this study aims to investigate the role of WA in lung cancer. Here, WA was shown to inhibit proliferation and invasion in lung cancer but induced apoptosis. Combined administration of WA with cisplatin (WA/cisplatin) showed better efficacy to inhibit proliferation and to induce apoptosis. The level of total ROS was increased by WA, and WA/cisplatin treatment exhibited higher ROS production. Furthermore, WA was shown to induce the activity of the caspase-3-mediated signaling pathway, and this activation was enforced by WA/cisplatin. In addition, the critical members in NFκB signaling pathway, such as p65, IKK, and HDAC, were decreased by WA when IκB was increased reversely. In conclusion, this study suggests that WA is a promising molecule harboring the activity to inhibit the progression of lung cancer and to increase the efficacy of cisplatin.
CircROBO2 Orchestrates Osimertinib Resistance Through miR-625-5p/PDGFB-Mediated MAPK Activation in Non-Small Cell Lung Cancer.
He M, Cai JY, Wang YY … +3 more , Ma X, You CG, Gao HW
IUBMB Life · 2025 Jul · PMID 40719479 · Publisher ↗
The emergence of acquired resistance to osimertinib represents a formidable therapeutic challenge in the management of non-small cell lung cancer (NSCLC). While circular RNAs (circRNAs) have been increasingly recognized...
The emergence of acquired resistance to osimertinib represents a formidable therapeutic challenge in the management of non-small cell lung cancer (NSCLC). While circular RNAs (circRNAs) have been increasingly recognized as crucial modulators of chemotherapeutic resistance, their specific involvement in osimertinib resistance mechanisms remains poorly elucidated. We established osimertinib-resistant NSCLC cell lines (HCC4006OR) through prolonged drug exposure and conducted comprehensive transcriptome sequencing to identify differentially expressed circRNAs. The molecular characteristics and functional implications of circROBO2 were systematically investigated utilizing an array of cellular and molecular biological methodologies. Advanced molecular dynamics simulations were implemented to elucidate the potential molecular interactions between PDGFB and osimertinib. We identified circROBO2 as significantly upregulated in osimertinib-resistant HCC4006OR cells. Functional studies revealed that circROBO2 enhances cell survival, proliferation, and invasion while suppressing apoptosis under osimertinib treatment. Mechanistically, circROBO2 functions as a molecular sponge for miR-625-5p, resulting in elevated PDGFB expression and subsequent activation of the MAPK pathway, particularly the RAF/MEK/ERK cascade. Targeting this pathway through circROBO2 knockdown or miR-625-5p overexpression partially restored osimertinib sensitivity in resistant cells. Molecular dynamics simulations suggested potential direct interactions between PDGFB and osimertinib, providing additional insights into the resistance mechanism. Our study identifies a novel circROBO2/miR-625-5p/PDGFB regulatory axis in osimertinib resistance and positions circROBO2 as a potential therapeutic target and biomarker for NSCLC treatment.
The IUBMB Focused Meeting on Aminoacyl-tRNA Synthetases 2023.
O'Donoghue P, Heinemann IU
IUBMB Life · 2025 Jul · PMID 40719009 · Publisher ↗
By ligating amino acids to their cognate transfer RNAs (tRNAs), the aminoacyl-tRNA synthetases (AARSs) establish the genetic code in all living cells. This special issue of IUBMB Life is dedicated to the IUBMB Focused Me...
By ligating amino acids to their cognate transfer RNAs (tRNAs), the aminoacyl-tRNA synthetases (AARSs) establish the genetic code in all living cells. This special issue of IUBMB Life is dedicated to the IUBMB Focused Meeting on AARSs in 2023 and includes 12 original research articles and reviews that demonstrate some of the significant advances in AARS biology that were featured at the meeting. The articles focus on the role of AARS variants in human disease, molecular evolution of AARSs, synthetic biology applications involving AARSs, and the roles of AARSs and tRNAs in regulating protein synthesis. Together these studies reveal an expanded understanding of the function of AARSs in diverse cells and organisms and the application of these discoveries to biotechnology and medicine.
MYC-Mediated Osseous Regeneration via BMSCs/PRP/β-TCP/PCL Bioprinted Constructs: Rapid Defect Rehabilitation and Preliminary Clinical Efficacy Evaluation.
Luo D, Ran Z, Wu J … +5 more , Wang L, Wu W, Xie K, Deng L, Hao Y
IUBMB Life · 2025 Jul · PMID 40718956 · Publisher ↗
Bone defects present significant clinical challenges due to their morphological heterogeneity and structural complexity, necessitating regenerative strategies that integrate structural adaptability, biomechanical stabili...
Bone defects present significant clinical challenges due to their morphological heterogeneity and structural complexity, necessitating regenerative strategies that integrate structural adaptability, biomechanical stability, and osteogenic potential. In this study, a bioengineered construct composed of bone marrow mesenchymal stem cells (BMSCs), platelet-rich plasma (PRP), polycaprolactone (PCL), and β-tricalcium phosphate (β-TCP) was fabricated using 3D bioprinting. In vitro assays assessed osteoprogenitor cell proliferation (CCK-8), migration (Transwell), differentiation (ALP staining), and endothelial tubulogenesis (Matrigel assay). In vivo bone regeneration was evaluated using a rabbit femoral condyle defect model, with histomorphometric analysis (Masson and COL-1 staining). Mechanistic insights were explored via RNA sequencing and western blot analysis. Clinical validation included pre- and postoperative assessments of visual analog scale (VAS) scores and computed tomography (CT) imaging in patients with osseous defects. The bioprinted constructs significantly enhanced BMSCs proliferation (p < 0.01), migration (p < 0.0001), and ALP activity (p < 0.0001), while promoting endothelial tubulogenesis (p < 0.01). In vivo, the BMSCs/PRP/PCL/β-TCP group exhibited greater Masson staining and collagen type I expression than controls at 2 weeks, 1 month, and 6 months postoperatively. Clinically, VAS scores significantly decreased (3.33 ± 1.63 pre-op vs. 0.50 ± 0.84 post-op, p = 0.005) with no severe complications. PRP concentration-dependently upregulated MYC expression (mRNA: p < 0.0001; protein: p < 0.0001), while MYC knockdown abrogated PRP-induced ALP and RUNX2 expression, confirming MYC's regulatory role in osteogenesis. In conclusion, BMSCs/PRP/PCL/β-TCP bioprinted constructs enhance MYC-mediated bone regeneration, demonstrating promising clinical potential for bone defect repair.
Deacetylase Inhibitor Trichostatin A Promotes the Proliferation of Epithelial Cells and Suppresses Glycolytic Activity of Fibroblasts in the Kidney.
Buyan MI, Pevzner IB, Buyan AI … +4 more , Zorova LD, Zorov DB, Andrianova NV, Plotnikov EY
IUBMB Life · 2025 Jul · PMID 40685571 · Publisher ↗
Undesirable tissue fibroblast activation after injury is still an unresolved problem for many organs, including the kidney. Kidney fibroblasts and tubular epithelial cells demonstrate significant differences in gene expr...
Undesirable tissue fibroblast activation after injury is still an unresolved problem for many organs, including the kidney. Kidney fibroblasts and tubular epithelial cells demonstrate significant differences in gene expression profiles, including metabolism-related genes. As a result, these cell types exhibit differences in the energy metabolism that could be the basis of targeted therapy for fibrosis. Among other deacetylase inhibition is considered a therapeutic approach that could simultaneously promote tissue regeneration and suppress the development of fibrosis, but their relation to bioenergetics has not been considered before. In this study, we aimed to compare the influence of the HDAC inhibitor trichostatin A (TSA) on renal tubular epithelial cells and kidney fibroblasts. We analyzed resemblance and differences in TSA effects on the proliferative activity of the cells and investigated the molecular mechanisms responsible for these effects; e.g., we focused on the activity of signaling pathways associated with cell viability (Akt/mTOR/p70). We found that TSA increased the proliferation rate of epithelial cells, while it tended to decrease the growth rate of fibroblasts. Furthermore, the amount of phosphorylated forms of kinases Akt and P70 increased in epithelial cells after incubation with TSA, indicating the activation of the Akt/mTOR/p70 signaling pathway, while decreasing its activity in fibroblast cells. Since there are differences in the bioenergetics between fibroblasts and epithelial cells, we investigated the impact of TSA on the glycolytic activity of both cell types. Indeed, we showed that TSA reduced the activity of glycolytic processes in fibroblast cells. The observed changes indicate a positive effect of TSA on regenerative versus fibrotic processes in the kidney by reducing the growth and metabolic activity of fibroblasts and activating the proliferation of epithelial cells.
Establishment of Initiated Cell Line Derived From NIH3T3 Fibroblasts.
Ro MH, Park T, Hwang S … +3 more , Kim HG, Lee M, Lee M
IUBMB Life · 2025 Jul · PMID 40673660 · Publisher ↗
Autophagy plays contrasting roles depending on the stage of cellular transformation. However, although advanced tumor cell models are abundant, cell lines at the initiation stage of transformation are very limited. There...
Autophagy plays contrasting roles depending on the stage of cellular transformation. However, although advanced tumor cell models are abundant, cell lines at the initiation stage of transformation are very limited. Therefore, the development of initiated cell lines-cells that have acquired early genetic alterations but not yet completed the multistep transformation process -is crucial for the development of anticancer drugs targeting autophagy. In this study, we successfully established a new initiated cell line (Foci #3) from foci formed in the in vitro two-stage cell transformation assay with NIH3T3 fibroblast cells. Foci #3 cells retained typical features of epithelial morphology, similar to its parental untransformed NIH3T3 cells. However, unlike NIH3T3 cells, where many dead cells were found during the long-term culture of 40 days, few dead cells were observed in Foci #3 cells. Particularly, the sensitivity of Foci #3 cells to the autophagy inhibitor CQ was higher than that of NIH3T3 cells and similar to that of Bhas 42 cells, the most commonly used initiated cell line. Moreover, Foci #3 cells maintained a higher level of autophagic flux than NIH3T3 cells throughout the extended culture period, indicating acquisition of the characteristic of dependence on autophagy for survival, which is typical of transformed cells. Importantly, qPCR analysis of epithelial-mesenchymal transition gene expression revealed that the Foci #3 cell line exhibited characteristics of both non-tumorigenic and tumorigenic states. Whole-genome sequencing analysis revealed that among the 17 genes with exon mutations in the Foci #3 cells, four were tumor suppressors and eight were involved in oncogenesis. Additionally, the Foci #3 cell line exhibited the loss of copy number variations in several tumor suppressors. Together, our results suggest that the newly developed Foci #3 cell line may be an efficient tool for elucidating the role of autophagy in the early stages of transformation.
A New Treatment Strategy for Lung Cancer With HDAC and Wnt/β-Catenin Pathway Inhibitors.
Erturk E, Akgun O, Yildiz Y … +2 more , Tuna G, Ari F
IUBMB Life · 2025 Jul · PMID 40650414 · Full text
Lung cancer is a type of cancer with high morbidity and mortality rates worldwide. The overall survival rate of lung cancer patients is low due to a lack of therapeutic options. Recently, the combination of histone deace...
Lung cancer is a type of cancer with high morbidity and mortality rates worldwide. The overall survival rate of lung cancer patients is low due to a lack of therapeutic options. Recently, the combination of histone deacetylase (HDAC) inhibitors with anti-cancer agents offers a promising therapeutic strategy for cancer treatment. Repurposing these drug combinations is important to evaluate their preventive effect on the epithelial mesenchymal transition (EMT) phenotype, which plays a critical role in tumor progression and metastasis. In this study, the changes that the combination of the HDAC inhibitor Valproic acid (VPA) and Wnt/β-Catenin pathway inhibitor Niclosamide (Niclo) may cause in cytotoxicity, apoptosis, cell cycle, and EMT mechanisms in lung cancer cell lines (A549 and H1299) were examined. According to the results, the combination of VPA + Niclo significantly reduced cell viability in lung cancer cells compared to the use of Niclo alone. ELISA and Western blot analyses revealed that the combination of VPA + Niclo significantly enhanced the total acetylation of Histone H3 compared to the use of VPA alone. It was also found that the combination treatment induced apoptosis by increasing the activity of Caspase 3/7 and Annexin-V and significantly increased the percentage of apoptotic cells by causing depolarization of mitochondria. After cell cycle analysis, the combination treatment increased G1 phase retention in A549 cells, while G1-G2/M phase retention increased in H1299 cells. Wound healing and transwell migration assay results showed that the VPA + Niclo combination treatment inhibited cell migration in lung cancer cells. According to Western blot and PCR results, after VPA + Niclo treatment, the increase in E-Cadherin levels and the decrease in β-Catenin, Fibronectin, Vimentin, and N-Cadherin levels at both protein and gene levels indicated that combination therapy may be useful in preventing the EMT process in lung cancer cells. As a result of the analyses, it was seen that VPA + Niclo combination therapy could play a critical role in preventing the acquisition of the mesenchymal phenotype, reducing cell migration and invasion ability, and preventing tumor cell survival and resistance to apoptosis. In conclusion, it was determined that VPA + Niclo combination treatment shows anticancer activity in lung cancer cells and is a promising approach that may have a synergistic effect in inhibiting EMT.
Underlining the Molecular Mechanism of Nonalcoholic Fatty Liver Disease and Coronary Artery Disease in Lipid Metabolism by Combining Multiple Sets of Data Sets.
Zheng W, Wang S, Wang H … +3 more , Xu C, Yin Q, Di H
IUBMB Life · 2025 Jul · PMID 40631874 · Full text
Nonalcoholic fatty liver disease (NAFLD) is closely associated with coronary artery disease (CAD); however, their shared genetic traits and molecular mechanisms in lipid metabolism remain unclear. In this study, we ident...
Nonalcoholic fatty liver disease (NAFLD) is closely associated with coronary artery disease (CAD); however, their shared genetic traits and molecular mechanisms in lipid metabolism remain unclear. In this study, we identified that the differentially expressed genes in NAFLD and CAD intersected with lipid metabolism genes to obtain three key genes-GPD1, MVK, and PIK3R2. Data from the GeneCards database indicated a significant correlation between NAFLD-related regulatory genes and the expression levels of these key genes. Notably, GPD1 showed a significant positive correlation with PNPLA3 (r = 0.715), while PIK3R2 exhibited a significant negative correlation with MIR21 (r = -0.691). Similarly, CAD regulatory genes were significantly correlated with the expression levels of these key genes; GPD1 showed a significant positive correlation with APOA1 (r = 0.751), and PIK3R2 had a significant negative correlation with LPA (r = -0.362). Additionally, single-cell sequencing analysis of NAFLD showed that GPD1, MVK, and PIK3R2 had higher activity in cells with a high expression of bile acid metabolism genes in the immune pathway. In CAD, GPD1 showed higher activity in cells with high oxidative phosphorylation in the immune pathway. Finally, we found that one drug interacted with MVK, while 38 drugs interacted with PIK3R2. This study highlights GPD1, MVK, and PIK3R2 as key genes involved in NAFLD, CAD, and lipid metabolism, suggesting potential targets for further mechanistic studies and novel therapeutic approaches for patients with NAFLD and CAD.
SPP1 Regulates SASP via the p53 Signaling Pathway to Affect ALI Progression.
Yuan C, Zhao S, Ma W … +3 more , Na H, Tan Q, Gao J
IUBMB Life · 2025 Jul · PMID 40583352 · Publisher ↗
Acute lung injury (ALI) is a condition with acute respiratory failure caused by various factors, characterized by severe hypoxemia and diffuse alveolar damage, involving multiple cytokines and signaling pathways. This st...
Acute lung injury (ALI) is a condition with acute respiratory failure caused by various factors, characterized by severe hypoxemia and diffuse alveolar damage, involving multiple cytokines and signaling pathways. This study investigates the role of secreted phosphoprotein 1 (SPP1) in ALI and explores its underlying mechanisms through a series of in vitro and in vivo experiments. Our results demonstrate that SPP1 expression is significantly upregulated in ALI animal models, correlating with increased oxidative stress and inflammatory responses. In LPS-induced lung injury models, elevated levels of malondialdehyde (MDA) and IL1β, along with decreased superoxide dismutase (SOD) levels, were observed, further confirming the active state of SPP1 in ALI. In vitro experiments using BEAS-2B cells revealed that LPS treatment increased IL1β and reactive oxygen species (ROS) levels while decreasing SOD levels, with concomitant upregulation of SPP1. SPP1 knockdown significantly inhibited these changes, directly confirming its regulatory role in ALI progression. We further explored the regulatory mechanisms of SPP1 on the senescence-associated secretory phenotype (SASP), a key pathological process in ALI. SA-β-GAL staining and γ-H2AX results indicated elevated cellular senescence in LPS-treated cells and ALI models. SPP1 knockdown reduced senescence markers, enhanced cell viability, decreased apoptosis, and improved cell proliferation capacity, suggesting that SPP1 promotes ALI via the SASP phenotype. Mechanistically, we found that SPP1 regulates ALI via the p53 signaling pathway. LPS treatment increased p-p53 levels, whereas SPP1 knockdown reduced p53 activation. The use of a p53 inhibitor further suppressed SASP and improved ALI-related indicators. Animal model validation corroborated these findings, showing that SPP1 knockdown and p53 inhibitor treatment reduced lung tissue damage and improved ALI-related indicators. Collectively, our study reveals a novel mechanism by which SPP1 regulates ALI progression via the p53 signaling pathway and SASP. This discovery not only enriches our understanding of ALI pathogenesis but also provides a new therapeutic target and potential intervention strategies for ALI treatment.
Fungi and Myxomycetes of the Tehuacán-Cuicatlán Biosphere Reserve, Mexico: A Comprehensive Review and Future Perspectives.
Mena-Portales J, Pérez-Llano Y, Vásquez-Dávila MA … +4 more , Cantillo T, Manzanero-Medina GI, Del Rayo Sánchez-Carbente M, Batista-García RA
IUBMB Life · 2025 Jun · PMID 40539492 · Full text
The Tehuacán-Cuicatlán Biosphere Reserve in Mexico, spanning approximately 10,000 km, is crucial for conserving arid and semi-arid ecosystems, as it hosts unique endemic species and complex ecological interactions. Despi...
The Tehuacán-Cuicatlán Biosphere Reserve in Mexico, spanning approximately 10,000 km, is crucial for conserving arid and semi-arid ecosystems, as it hosts unique endemic species and complex ecological interactions. Despite their environmental significance, fungi and myxomycetes in this region have been understudied, particularly those adapted to extreme conditions. These organisms are vital for nutrient cycling, soil stability, and plant health, making them excellent bioindicators for monitoring ecosystem health and detecting environmental changes. However, challenges such as limited historical data, remote fieldwork, and advanced identification techniques complicate their study. Based on a review of mycological literature and various biodiversity databases, the first inventory of fungi and myxomycetes of the Tehuacán-Cuicatlán Biosphere Reserve (Tehuacán Desert) was prepared in this work. This inventory lists 436 taxa of organisms traditionally identified as fungi, belonging to 254 different genera. Of these, 266 taxa belong to 214 genera of fungi sensu stricto, and 170 taxa from 40 genera of myxomycetes. Fungal and myxomycete communities must be documented, and their inherent variability understood through baseline research. Research on fungal adaptation to shifting environments in the Tehuacán Valley may reveal resilience mechanisms in desert ecosystems. Fungi and myxomycetes are useful bioindicators for assessing ecosystem health and ecological alterations under global climate stress, due to their rapid environmental response. Understanding these adaptive strategies helps preserve the environment, produce new drugs, and foster agricultural resilience. Polyextremotolerant and extremophilic fungi are studied in the reserve to understand the boundaries of life and survival processes. To use fungi to protect sensitive ecosystems and mitigate climate change in the Tehuacán-Cuicatlán Biosphere Reserve, interdisciplinary collaboration and innovative methods are needed. The Tehuacán Desert can be considered a natural laboratory for studying polyextremotolerant and extremophilic fungi.
Single-Cell Profiling of the Microenvironment in High-Risk Neuroblastoma.
Xu Y, Ding J, Shi Z … +1 more , Bao L
IUBMB Life · 2025 Jun · PMID 40536225 · Publisher ↗
Although tumor biology and treatment of neuroblastoma (NB) have substantially advanced, the clinical outcomes of patients with high-risk NB (HR-NB) still remain unsatisfactory. Increasing evidence suggests that targeting...
Although tumor biology and treatment of neuroblastoma (NB) have substantially advanced, the clinical outcomes of patients with high-risk NB (HR-NB) still remain unsatisfactory. Increasing evidence suggests that targeting the tumor microenvironment (TME) is an effective strategy for the treatment of patients with HR-NB, highlighting the necessity to deepen the understanding of the complex TME in HR-NB. We analyzed the single-cell RNA sequencing data of 16 NB samples from 11 patients with HR-NB and 5 patients with intermediate-/low-risk NB. We found that proliferating CD8+ TUBA1B+ T cells, H2AFZ+ macrophages, and proliferating HMGB2+ B cells were particularly enriched in HR-NB samples and played an immunosuppressive role. LAG3 and HAVCR2 could serve as potential immunotherapeutic targets for HR-NB. SCENIC analysis innovatively revealed that proliferating HMGB2+ B cells had a special differentiation process compared with that of plasma cells. H2AFZ+ macrophages evolved from monocytes and M1-like macrophages and exhibited an M2-like phenotype. HR-NB-enriched cancer-associated fibroblasts and endothelial cells were related to tumor migration and progression. An immune-related risk model based on five genes (BIRC5, UBE2C, CDKN3, TK1, and PTTG1) was constructed in the training set and applied to the validation set. Both sets showed a promising clinical prediction value. In sum, this study preliminarily revealed the landscape of the TME in HR-NB at a single-cell level; several TME cell clusters that could inhibit immune activities or promote tumor progression in HR-NB were determined, thereby providing novel immunotherapeutic targets and an immune-related prognostic signature for HR-NB and promoting the development of immunotherapy of HR-NB.
Modulation of PPAR-α and PPAR-γ Influences Cardiomyocyte Growth and Cardiac Remodeling.
Xuan Q, Li J, Feng Z … +6 more , Zhu L, Jiang T, Li H, Liu M, Qian X, Ma X
IUBMB Life · 2025 Jun · PMID 40536211 · Publisher ↗
Peroxisome proliferator-activated receptors (PPARs), particularly PPAR-α and PPAR-γ, are key regulators of cardiac energy metabolism and have been implicated in cardiac remodeling. However, their roles in cardiomyocyte p...
Peroxisome proliferator-activated receptors (PPARs), particularly PPAR-α and PPAR-γ, are key regulators of cardiac energy metabolism and have been implicated in cardiac remodeling. However, their roles in cardiomyocyte proliferation and hypertrophy remain incompletely understood. In this study, we investigated the effects of PPAR-α and PPAR-γ modulation on neonatal rat cardiomyocytes (NRCMs) using pharmacological agonists (WY-14643 for PPAR-α and pioglitazone for PPAR-γ) and inhibitors (MK-886 for PPAR-α and GW9662 for PPAR-γ), as well as siRNA-mediated knockdown approaches. Cardiomyocyte proliferation and hypertrophy were assessed by immunofluorescence, cell size measurements, and proliferation assays. Our findings demonstrate that PPAR-α activation significantly promotes cardiomyocyte proliferation and reduces hypertrophy, whereas PPAR-α inhibition induces hypertrophic changes and suppresses proliferation. Similarly, PPAR-γ activation enhances both proliferation and hypertrophy of cardiomyocytes, suggesting its involvement in physiological hypertrophy and a potential protective role in pathological remodeling. In contrast, pharmacological activation or genetic inhibition of PPAR-δ showed no significant effects on cardiomyocyte proliferation or hypertrophy, highlighting its distinct role in metabolic homeostasis rather than structural remodeling. PPAR-α and PPAR-γ play distinct but complementary roles in regulating cardiomyocyte proliferation and hypertrophy. These results suggest that targeting PPAR-α and PPAR-γ may represent promising therapeutic strategies for cardiac hypertrophy and heart failure. Further in vivo studies are warranted to clarify their molecular mechanisms and potential clinical applications.
Euryhaline Black Yeasts From the Arabian Gulf: Descriptions of Salinomyces qatarensis sp. nov. and Hortaea werneckii Genotypic Variations.
Fotedar R, Zalar P, Al Malaki A … +6 more , Al Zeyara A, Kaul R, Kolecka A, Fell JW, Boekhout T, Gunde-Cimerman N
IUBMB Life · 2025 Jun · PMID 40530903 · Publisher ↗
The Arabian Gulf surrounding Qatar is an oligotrophic marine environment characterized by extreme conditions, such as increased water temperatures and high salinity compared to other semi-enclosed seas, such as the Medit...
The Arabian Gulf surrounding Qatar is an oligotrophic marine environment characterized by extreme conditions, such as increased water temperatures and high salinity compared to other semi-enclosed seas, such as the Mediterranean Sea. Thirty-six black yeast-like isolates were obtained from marine waters surrounding Qatar, representing 4% of all isolated yeasts. DNA sequence analysis of the internal transcribed spacers (ITS1, ITS2), the 5.8S rRNA gene, and the D1/D2 domains of the LSU rDNA identified 20 isolates as Hortaea werneckii, and 15 (75%) of them represent previously unknown genotypes with a wide NaCl tolerance at 37°C. In addition, 16 meristematic black yeast-like cultures were isolated that grew as multi-cellular bodies and reproduced by endoconidiation. Phylogenetic analysis based on the D1/D2 domains of LSU rDNA, partial sequences of the second largest subunit of RNA polymerase II (RPB2) and translation elongation factor 1-alpha (TEF) of selected representative strains of Dothideomycetes and of morphologically similar taxa, Pseudotaeniolina globosa and Trimmatostroma salinum, supported the proposal of meristematic black yeast-like cultures as a new species, Salinomyces qatarensis sp. nov., within Teratosphaeriaceae, Mycosphaerellales. The holotype is designated as CBS 150510, with ex-type strains EXF-15246 and QCC/Y38/18, and the species is registered in Mycobank as MB#848869. In addition, based on the above molecular analysis, a new combination was proposed for an euryhaline fungus from Mediterranean salterns, Trimmatostroma salinum, into the genus Verrucocladosporium as V. salinum, MB#856063. This study increases our knowledge of the distribution and genetic diversity of Hortaea werneckii, the etiological agent of tinea nigra. In addition, the description of S. qatarensis and the combination of euryhaline T. salinum to Verrucocladosporium provides support for halotolerance as one of the traits in Dothideomycetes.
Squalene: A High-Value Compound for COVID-19 Vaccine Adjuvants and Beyond Pathways, Production Strategies, and Market Potential.
Dasari D, Singhania RR, Bhatia SK … +2 more , Dong CD, Patel AK
IUBMB Life · 2025 Jun · PMID 40530893 · Publisher ↗
Squalene, a naturally occurring triterpene, has gained significant attention due to its critical role as an adjuvant in COVID-19 vaccines and its broad applications in pharmaceuticals, cosmetics, and nutraceuticals. This...
Squalene, a naturally occurring triterpene, has gained significant attention due to its critical role as an adjuvant in COVID-19 vaccines and its broad applications in pharmaceuticals, cosmetics, and nutraceuticals. This review explores the potential of squalene production, prompting a shift toward sustainable and innovative approaches. Key biosynthetic pathways across various organisms, including plants, fungi, and microalgae, are analyzed to identify efficient production systems as compared to fast-growing heterotrophic thraustochytrids. Advanced strategies to enhance squalene yields are explored, including the use of chemical enhancers (methyl jasmonate), antioxidants (alpha-tocopherol), cofactor recycling, and squalene epoxidase inhibitors (terbinafine). Additionally, the global market potential of squalene is assessed, highlighting its economic importance and growing demand in the healthcare and cosmetic industries. The challenges of large-scale squalene production are addressed with a focus on sustainable alternatives to shark-derived sources as a high ethical concern. By aligning with Sustainable Development Goals (SDG-3: Good Health and Well-Being), squalene production supports advancements in vaccine development and biotechnological innovations. Future opportunities are highlighted, including novel applications in cancer therapy, functional foods, and anti-aging products, offering pathways to harness its full potential while contributing to a sustainable bioeconomy.
Tyrosine and Phenylalanine Activate Neuronal DNA Repair but Exhibit Opposing Effects on Global Transcription and Adult Female Mice Are Resilient to TyrRS/YARS1 Depletion.
Jhanji M, Bhan A, Arrowood C … +9 more , Yakout DW, Shroff A, McManus D, Gifford H, Vacharasin J, Lizarraga SB, Nazarko TY, Mabb AM, Sajish M
IUBMB Life · 2025 Jun · PMID 40476370 · Full text
Serum tyrosine and phenylalanine levels increase during aging and age-associated disorders. We previously showed that tyrosyl-tRNA synthetase (TyrRS/YARS1) is reduced in Alzheimer's Disease (AD) brains, and tyrosine and...
Serum tyrosine and phenylalanine levels increase during aging and age-associated disorders. We previously showed that tyrosyl-tRNA synthetase (TyrRS/YARS1) is reduced in Alzheimer's Disease (AD) brains, and tyrosine and phenylalanine decrease TyrRS in neurons. Here, we found that tau is a negative regulator, whereas estrogen and leucine act as positive regulators of TyrRS. Young female mice exhibit increased TyrRS in the cortex compared to male mice. Notably, young Tau knockout male, but not female mice showed increased cortical TyrRS. Tau accumulation in middle-aged female mice did not decrease cortical TyrRS compared to males, suggesting that middle-aged females are resilient to tau-mediated TyrRS depletion. Tyrosine and phenylalanine treatment decreased tubulin tyrosination, activated DNA repair pathways, and protected against etoposide (ETO) and camptothecin (CPT)-induced toxicity, respectively, in neurons. While tyrosine facilitated topoisomerase 1 (TOP1) recruitment to chromatin and inhibited global transcription, in contrast, phenylalanine recruited topoisomerase 2 beta (TOP2β) to chromatin and stimulated global transcription. Furthermore, tyrosine decreased the presence of DNA fragments in a comet assay whereas phenylalanine increased them. Addition of cis-resveratrol (cis-RSV) protected against tyrosine-induced transcription inhibition by facilitating the recruitment of both TOP1 and TOP2β to chromatin and increasing tubulin tyrosination. Moreover, cis-RSV decreased both total and phosphorylated tau and protected neurons against amyloid beta (Aβ)-induced neurite degeneration and DNA damage. Gene expression profiling using human embryonic stem cell (hESC)-derived neurons demonstrated that cis-RSV is a broad-spectrum neuroprotective and anti-viral agent. In contrast, trans-RSV mimics phenylalanine-induced gene expression, including downregulation of long genes and induction of an AD-like gene expression signature. This work suggests that age and disease-associated increases in serum tyrosine and phenylalanine levels would activate neuronal DNA repair while inhibiting transcription and tubulin tyrosination. cis-RSV protects against their toxicity by restoring tubulin tyrosination, TOP1 and TOP2β-mediated transcription, and decreasing tau in primary neurons.
Nonsense Mutations in Rare and Ultra-Rare Human Disorders: An Overview.
Vitale E, Ricci D, Corrao F … +6 more , Fiduccia I, Cruciata I, Carollo PS, Branchini A, Lentini L, Pibiri I
IUBMB Life · 2025 Jun · PMID 40474765 · Full text
Over 7000 rare diseases have been described, collectively affecting 350 million people worldwide. Most of these conditions result from nonsense mutations, representing approximately 10% of all genetic mutations associate...
Over 7000 rare diseases have been described, collectively affecting 350 million people worldwide. Most of these conditions result from nonsense mutations, representing approximately 10% of all genetic mutations associated with human inherited diseases. Nonsense mutations convert a sense codon into a premature termination codon (PTC), leading to premature translation termination and the production of truncated, nonfunctional proteins. This results in a loss-of-function phenotype in many genetic disorders, contributing to the disease's severity and progression. The molecular mechanisms of PTC formation involve various genetic alterations, including single-nucleotide changes, frameshifts, and splicing mutations. The nonsense-mediated mRNA decay (NMD) pathway degrades mRNAs containing premature termination codons (PTCs). In contrast, 25% of PTC mRNAs, depending on the PTC position and cellular context, can evade NMD, resulting in the synthesis of truncated proteins. A termination codon during translation is essential for proper protein synthesis, and translational readthrough-a process in which the ribosome bypasses the PTC and reaches the natural stop codon-may restore some level of protein function. The effectiveness of readthrough depends on the surrounding genetic context and the type of amino acid incorporated at the PTC position. This review aims to explore the molecular characteristics of nonsense-related diseases (NRDs), including cystic fibrosis, hemophilia, Fabry disease, choroideremia, Usher syndrome, Shwachman-Diamond syndrome, and certain hereditary neuropathies and cancers.
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