IUBMB Life [JOURNAL]
Sun
200 papers
Cellular Mechanisms and Therapeutic Targeting of Long Noncoding RNAs in Atherosclerotic Disease.
Abu-Khudir R, Doghish AS, Abd-Elmawla MA … +7 more , Ghaiad HR, Aborehab NM, Zaki MB, Mohamed HH, Mohammed OA, Hamad RS, Elimam H
IUBMB Life · 2026 Feb · PMID 41681047 · Publisher ↗
To effectively combat atherosclerotic diseases, it is essential to identify novel biomarkers and therapeutic targets that can detect early-stage atherosclerosis before the development of high-risk, unstable plaques. Due...
To effectively combat atherosclerotic diseases, it is essential to identify novel biomarkers and therapeutic targets that can detect early-stage atherosclerosis before the development of high-risk, unstable plaques. Due to their distinct chemical and biological characteristics, long noncoding RNAs (lncRNAs) have emerged as promising biomarkers for various diseases. This review highlights the potential therapeutic intervention targeting lncRNAs in atherosclerosis. Recent research has pointed out the significant role of lncRNAs in the pathogenesis and progression of atherosclerosis, influencing endothelial dysfunction in both proliferation and migration, lipid metabolism, and plaque stability through diverse molecular mechanisms such as NEAT1, lincRNA-p21, MALAT1, H19, GAS5, MEG3, HOTAIR, and TUG1. This study also emphasizes the role of lncRNAs in the diagnosis and prognosis of atherosclerosis, such as APPAT, MALAT1, MIAT, SOX2-OT, HIF1A-AS1, lncRNA-ATB, PVT1, NORAD, HOTAIR, H19, LIPCAR, and DANCR. The research highlighted the therapeutic intervention targeting various lncRNAs in atherosclerosis via different signaling pathways, such as TNF-α, JAK/STAT, IFN-γ signaling, ROCK1, AP1, and NF-κB signaling, PI3K/AKT/mTOR, which holds a new class of RNA-based therapeutics. The research aims to elucidate the crucial roles of lncRNAs in regulating gene expression and cellular processes involved in atherosclerosis development, which could emerge as potential therapeutic targets for atherosclerosis.
ADAM15 Is a Potential Biomarker for Pan-Cancer Prognosis and Immunotherapy: Validation in HCC and COAD.
Guo W, Liu Y, Ma W … +3 more , Fan L, Chen B, Wang J
IUBMB Life · 2026 Feb · PMID 41630479 · Publisher ↗
A Disintegrin and metalloprotease (ADAM) family encompasses a diverse array of widely expressed proteases functioning in pathological processes. ADAM15 stands out as a pivotal mediator in multiple tumor types, responding...
A Disintegrin and metalloprotease (ADAM) family encompasses a diverse array of widely expressed proteases functioning in pathological processes. ADAM15 stands out as a pivotal mediator in multiple tumor types, responding to immune checkpoint inhibitors (ICI) significantly. By promoting pro-angiogenic genes, potentiating integrin binding as well as modulating the inflammatory response, ADAM15 orchestrates cellular adhesion and migration, thereby fostering tumor progression. Despite these compelling insights, the intricate roles of ADAM15 in prediction, immune modulation, and therapeutic targeting among malignant disorders remain largely unexplored. To decipher the pan-cancer landscape of ADAM15, we integrated data from multiple databases. Immunohistochemical profiles of ADAM15 were retrieved from the human protein atlas (HPA) database. Furthermore, the tumor immune estimation resource (TIMER) and the ESTIMATE (Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression data) algorithm were harnessed to dissect the immune infiltration patterns and immune checkpoint genes associated with ADAM15. The tumor immune single-sample gene set enrichment analysis (TISMO) was employed to explore the impact of ADAM15 on the tumor immune microenvironment. Additionally, drug sensitivity analysis and subsequent molecular docking studies were conducted to identify potential therapeutic compounds targeting ADAM15. These findings were rigorously validated through reverse transcription-polymerase chain reaction (RT-PCR), western blotting (WB), and immunohistochemistry (IHC) by cell lines and clinical samples from hepatocellular carcinoma (HCC) as well as colon adenocarcinoma (COAD). Our comprehensive analysis revealed that ADAM15 is markedly upregulated in diverse cancer types. IHC, WB, and RT-PCR assays of HCC and COAD confirmed these findings. Notably, elevated ADAM15 correlates with adverse prognosis in pan-cancer, positioning it as a promising novel biomarker. Drug sensitivity profiling unveiled a positive and statistically significant association between ADAM15 and AZD-8055 and Nitazoxanide, whereas a negative correlation was observed with Oxaliplatin and Ponatinib. These findings were further corroborated by molecular docking simulations, highlighting the potential of these compounds as therapeutic targets for ADAM15-driven cancers. Our study underscores the multifaceted role of ADAM15 in cancer progression, immune evasion, and response to therapy. By elucidating the intricate interplay between ADAM15 and the tumor microenvironment (TME), we have identified novel diagnostic biomarkers and potential therapeutic avenues.
Punicalagin Targets FDX1 to Induce Cuproptosis for the Treatment of Gastric Cancer.
Fang YY, Zhang SY, Leng CY … +7 more , Jing-Lv, Zhao SF, Sun XY, Xin-Li, Lu YY, Bing-Wang, Qi WW
IUBMB Life · 2026 Jan · PMID 41589439 · Publisher ↗
Gastric cancer represents the fifth most common malignancy globally and the third leading cause of cancer-related deaths. Due to its insidious early symptoms and frequent metastasis at diagnosis, the survival rate remain...
Gastric cancer represents the fifth most common malignancy globally and the third leading cause of cancer-related deaths. Due to its insidious early symptoms and frequent metastasis at diagnosis, the survival rate remains dismal. There is thus an urgent clinical need for novel therapeutic agents. Innovative strategies combining traditional chemotherapy with interventions that induce novel cell death pathways represent a promising translational direction for improving patient outcomes. Punicalagin (PUN), a natural polyphenol derived from pomegranate, exhibits potent antioxidant and broad-spectrum antitumor activities, yet its role in gastric cancer remains understudied. Three gastric cancer cell lines (AGS, HGC27, MFC) and one normal gastric mucosal epithelial cell line (GES-1) were initially selected for in vitro experiments. The effects of PUN on gastric cancer cells and normal gastric mucosal epithelial cells were assessed through MTT assay, propidium iodide (PI) staining, and cell colony formation assays, while cell migration ability was evaluated using a scratch wound healing assay. The inhibitory effect of PUN on gastric cancer was tested in a subcutaneous tumor model in nude mice, with pathological changes in vital tissues and organs observed via hematoxylin and eosin (H&E) staining. Subsequently, transcriptome sequencing was performed, and JC-1, H2DCFDA, and DHE staining methods were employed to measure mitochondrial function and reactive oxygen species (ROS) levels in PUN-treated cells. Western blotting was used to detect the expression of apoptosis- and cell cycle-related proteins. Next, two gastric cancer cell lines (AGS, HGC27) were selected for in vitro experiments to assess the combined effects of PUN and the copper ionophore elesclomol (ES) (hereafter referred to as ES-Cu, representing the combination of ES and Cu). Cell viability was assessed using the MTT assay, and morphological changes were observed under a microscope. Cell proliferation and migration abilities were assessed via colony formation and scratch wound healing assays, respectively. Fluorescence staining was used to examine mitochondrial function and ROS levels in cells co-treated with PUN and ES-Cu. Laser confocal microscopy and Western blotting were employed to determine the oligomerization level of DLAT protein by quantifying soluble and insoluble protein expression, along with the expression of ACO2, ETFDH, FDX1, and LIAS proteins. Molecular docking, molecular dynamics simulations, immunofluorescence staining, and transfection techniques were utilized to confirm the critical role of FDX1 in copper-induced cell death following co-treatment with PUN and ES-Cu. We found that PUN could suppress the viability, proliferation, and migration of gastric cancer cells in a concentration- and time-dependent manner. Subsequent in vivo experiments demonstrated that PUN inhibited tumor growth in nude mice at a safe dosage. Besides, transcriptome sequencing and Western blot analysis revealed that PUN induced cell cycle arrest and apoptosis. Secondly, the cell death mechanism triggered by PUN was closely associated with mitochondrial stress. PUN increased intracellular ROS levels and reduced mitochondrial membrane potential. Transcriptome sequencing and proteomic analysis further revealed molecular changes at both the mRNA and protein levels, with differential gene analysis identifying potential targets and pathways. Moreover, when PUN was combined with ES-Cu, cell viability, proliferation, and migration were all suppressed, while exacerbating mitochondrial dysfunction and elevated oxidative stress. Laser confocal microscopy and Western blotting were used to assess the expression of soluble and insoluble proteins, confirming the oligomerization of the DLAT protein. Western blot also showed that PUN could regulate the expression levels of ACO2, ETFDH, FDX1, and LIAS proteins. Molecular docking, molecular dynamics simulations, and siRNA transfection were performed to confirm the critical role of ferredoxin 1 (FDX1) in copper-induced cell death. Furthermore, when used in combination with chemotherapy drugs, PUN exhibited synergistic inhibitory effects on gastric cancer growth. PUN demonstrates significant antitumor activity both in vivo and in vitro by inducing mitochondrial dysfunction, which subsequently triggers apoptosis. In combination therapy strategies, PUN can work synergistically with chemotherapy drugs to suppress gastric cancer growth. Furthermore, PUN enhances its inhibitory effect on gastric cancer by working synergistically with cuproptosis through targeting FDX1.
Balancing Promise and Peril: Hemophilia Gene Therapy Insights.
Akula S, Borroni E, Cottonaro A … +2 more , Follenzi A, Merlin S
IUBMB Life · 2026 Jan · PMID 41549917 · Full text
Hemophilia is an inherited disorder characterized by impaired blood clotting caused by mutations in the genes responsible for producing coagulation factor (F) VIII (hemophilia A, HA) or FIX (hemophilia B, HB). Current tr...
Hemophilia is an inherited disorder characterized by impaired blood clotting caused by mutations in the genes responsible for producing coagulation factor (F) VIII (hemophilia A, HA) or FIX (hemophilia B, HB). Current treatment primarily relies on replacement therapy, involving frequent and costly infusions of FVIII or FIX concentrates. While effective, these treatments come with the risk of developing neutralizing antibodies (inhibitors) against the infused factor. In recent years, non-factor replacement therapies have emerged as innovative treatment options, offering enhanced efficacy especially for patients with inhibitors. Despite their advantages, these approaches still fall short of providing a definitive, long-term cure. Since hemophilia is a monogenic disease, it presents an excellent opportunity for cell and gene therapy approaches aimed at achieving durable treatment and potentially a cure. Over the past three decades, remarkable advancements have been made in hemophilia gene therapy, culminating in the approval of Valoctocogene roxaparvovec (ROCTAVIAN, AAV-FVIII) and Etranacogene dezaparvovec (HEMGENIX, AAV-FIX) for patients with severe HA and HB, respectively. Nevertheless, gene therapy poses questions regarding its long-term efficacy and safety. This review synthesizes findings from clinical trials, addresses persistent challenges in hemophilia gene therapy, and underscores the biological constraints and limitations inherent to viral vector-based approaches.
Exosomal LncRNAs in Myocardial Ischemia: From Diagnostic Advantage to Therapeutic Targets.
Alshahrani MY, AlKhafaje Z, Hussein UA … +7 more , Adel Z, Alkadir OKA, Aldulaimi A, Jameel RK, Albadr RJ, Alwan M, Smerat A
IUBMB Life · 2026 Jan · PMID 41508694 · Publisher ↗
Myocardial ischemia (MI), which is a key form of ischemic heart disease, is still the most common cause of morbidity and mortality in the world. While reperfusion therapy has changed clinical management, many of the unme...
Myocardial ischemia (MI), which is a key form of ischemic heart disease, is still the most common cause of morbidity and mortality in the world. While reperfusion therapy has changed clinical management, many of the unmet needs for the early diagnosis and treatment of MI remain. Two rapid advances, namely, extracellular vesicle biology and the field of non-coding RNA genomics, have combined to identify a class of potent signaling molecules, exosomal long non-coding RNAs (lncRNAs). In this review, we characterize the specific functions of prominent exosomal lncRNAs in the core biological pathophysiological elements of MI, including apoptosis, inflammation, angiogenesis, autophagy, and fibrosis. Exosomal lncRNAs can either be involved in damaging - transmitting signals of injury-or restorative-driving repair and regeneration-and often play such roles based on their source and recipient. In addition to their therapeutic advantage, exosomal lncRNAs have enormous diagnostic capacity as stable, sensitive, and early-stage "liquid biopsy" diagnostics. By integrating core biology into clinical possibilities, we hope this review represents the field's current viewpoint and where it is heading to change the diagnosis and treatment of myocardial ischemia.
AdipoRon Suppresses Multiple Myeloma Proliferation Through AMPK-Mediated Metabolic Reprogramming and Apoptosis Induction.
Wang Z, Su X, Guo R … +2 more , Han Y, Zhang J
IUBMB Life · 2026 Jan · PMID 41503835 · Publisher ↗
Multiple myeloma (MM) remains an incurable hematologic malignancy, necessitating novel therapeutic strategies. This study investigates the clinical significance of adiponectin receptors and the anti-myeloma efficacy of t...
Multiple myeloma (MM) remains an incurable hematologic malignancy, necessitating novel therapeutic strategies. This study investigates the clinical significance of adiponectin receptors and the anti-myeloma efficacy of their agonist, AdipoRon. Bioinformatic analysis of GEO datasets (GSE124489, GSE187009) revealed significant downregulation of ADIPOR1 and ADIPOR2 in MM patients. Low expression of ADIPOR1 correlated with poor prognosis. Functionally, AdipoRon exerted potent anti-proliferative effects on MM cell lines (U266, RPMI8226) in time- and dose-dependent manners. Mechanistic studies demonstrated that AdipoRon induced mitochondrial apoptosis, evidenced by increased cleavage of PARP and Caspase-9, and triggered G0/G1 cell cycle arrest. At the signaling level, AdipoRon activated the AMPK pathway while concurrently suppressing AKT phosphorylation. The critical role of AMPK was confirmed through pharmacological approaches: the AMPK activator AICAR mimicked AdipoRon's effects, whereas the AMPK inhibitor Compound C partially reversed them. Further investigation identified acetyl-CoA carboxylase (ACC) as a key downstream effector, with ACC inhibition (TOFA) recapitulating AdipoRon's anti-MM effects. Specifically, AdipoRon preferentially suppressed ACC1 expression and subsequently downregulated CPT1A, indicating disruption of fatty acid metabolism. These findings establish that AdipoRon suppresses MM progression through AMPK-driven metabolic reprogramming and apoptosis induction, positioning adiponectin receptor agonism as a promising therapeutic strategy for multiple myeloma.
Capturing the Variations in Mutant p53-Driven Regulatory Networks in Breast Cancer Subtypes, Its Clinical Relevance and a Novel Association With Androgen Receptor and EMT.
Singh A, Gupta R, Kulshreshtha R
IUBMB Life · 2026 Jan · PMID 41472467 · Publisher ↗
The tumour suppressor TP53 is frequently mutated in breast cancer and drives poor outcomes. The impact of mutant p53 (mutp53) on subtype-specific gene and non-coding RNA networks, and their clinical significance, remains...
The tumour suppressor TP53 is frequently mutated in breast cancer and drives poor outcomes. The impact of mutant p53 (mutp53) on subtype-specific gene and non-coding RNA networks, and their clinical significance, remains largely underexplored. Here, using TCGA-BRCA data, we have delineated subtype-specific mRNA, lncRNA, and microRNA signatures, pathways, co-expression/interaction networks, and prognosis associated with hotspot mutp53 or wildtype p53 tumours. Our study shows that mutp53 deregulates the genes related to EMT, chemoresistance, and prognosis in a subtype-specific manner. The EMT-associated signature was able to stratify HER2 and Basal patients by their p53 status. Construction of lncRNA-mRNA-miRNA interaction networks led to the identification of various feedback loops and hub genes with prognostic relevance that possess binding sites for p53 and EMT-TFs within their promoters. In the basal mutp53 tumours, we found Androgen Receptor (AR) to be a downregulated EMT-associated gene, with its higher levels linked to a better prognosis. We validated that mutp53 breast cancer cell lines show reduced levels of AR and its predicted transcriptional target, miR-196a-5p. Overexpression of WTp53 resulted in the upregulation of AR and miR-196a-5p, while mutp53 (R175H) suppressed their expression. Basal mutp53 tumours with low AR displayed higher EMT scores. Enforced expression of AR led to suppression of mesenchymal markers in basal cell lines. Overall, we have identified novel prognostically relevant RNA signatures and networks that may serve as attractive therapeutic targets in mutp53 breast cancer patients in a subtype-specific manner. Additionally, we have discovered a novel AR:mutp53 association that may be implicated in EMT and chemoresistance.
Multi-Omics Analysis Reveals That the MAZ/HDGF Regulatory Axis Drives High-Grade Serous Ovarian Cancer Progression by Modulating Glycolysis and M2 Macrophage Polarization.
Liu J, Luo YH, Wan S … +1 more , Ni GT
IUBMB Life · 2026 Jan · PMID 41467359 · Publisher ↗
Super-enhancers (SEs) are large clusters of enhancers that drive high-level expression of genes critical for normal development and tumorigenesis. However, their precise roles in high-grade serous ovarian carcinoma (HGSO...
Super-enhancers (SEs) are large clusters of enhancers that drive high-level expression of genes critical for normal development and tumorigenesis. However, their precise roles in high-grade serous ovarian carcinoma (HGSOC) remain unclear. This study integrated SE-derived regulatory networks with proteomic profiles to identify key pro-tumorigenic signaling in HGSOC progression. Weighted gene co-expression network analysis (WGCNA) and machine learning were used to screen SE-driven core oncoproteins. The influence on cell phenotypes was evaluated by detecting invasion, proliferation, apoptosis, glucose consumption, lactate generation, and tube formation. M2 macrophage polarization was assessed by detecting CD163 cell proportion and TGF-β1 and IL-10 secretion. The MAZ/HDGF interaction was confirmed by luciferase and ChIP-qPCR assays. Xenograft studies were used to evaluate the in vivo function. HDGF was overexpressed and was identified as a core SE-driven oncoprotein in HGSOC. Silencing of HDGF inhibited the invasion, proliferation, and glycolysis of HGSOC cells, promoted their apoptosis, and attenuated HUVEC tube formation and M2 macrophage polarization. Mechanistically, MAZ transcriptionally activated HDGF through promoter binding. Moreover, HDGF re-expression counteracted the suppressive effects of MAZ knockdown on HGSOC cell malignant behaviors, HUVEC tube formation, M2 macrophage polarization, and the growth of xenograft tumors. In conclusion, our study unveils the MAZ/HDGF axis as a novel SE-mediated oncogenic pathway in HGSOC, providing previously unrecognized insights into SE-driven oncogenesis and highlighting potential targets for HGSOC treatment.
Effects of Methylglyoxal on Intestinal Cells: Insights on Epigenetic Regulatory Enzymes.
Morresi C, Feliziani G, Bellachioma L … +6 more , Giommi C, Gabbianelli R, Bordoni L, Ferretti G, Bacchetti T, Damiani E
IUBMB Life · 2025 Dec · PMID 41355505 · Full text
Methylglyoxal (MGO) is endogenously produced under physiological conditions as a by-product of glycolysis and by autooxidation of glucose and lipid peroxidation. The digestive system can also take up MGO from exogenous s...
Methylglyoxal (MGO) is endogenously produced under physiological conditions as a by-product of glycolysis and by autooxidation of glucose and lipid peroxidation. The digestive system can also take up MGO from exogenous sources, especially from ultra-processed foods. MGO is a highly reactive molecule, able to react with macromolecules forming covalent adducts resulting in advanced glycation end-products formation. MGO can also enter the nucleus and react with nucleic acids with the formation of MGO-nucleic acid adducts. The intestinal epithelium is continuously exposed to dietary and endogenous stimuli, including MGO, but the potential harmful role of MGO at the intestinal level has been poorly investigated. Therefore, the aim of the study was to further investigate the effects of MGO in intestinal cells and the molecular mechanisms involved, with particular attention to epigenetic regulatory enzymes such as histone deacetylases (HDAC), ten-eleven translocation (TET) family enzymes, and DNA methyltransferases (DNMT). Our results demonstrate that MGO exposure induces alterations in intestinal barrier function in differentiated Caco-2 cells monolayers. Moreover, MGO treatment induces cell apoptosis associated with an increase in cytosolic and mitochondrial reactive oxygen species. MGO-induced oxidative stress was associated with activation of the NFκB pathway and increased levels of proinflammatory molecules such as TNF-α and antioxidant enzymes (superoxide dismutase 1 [SOD1] and catalase). The increased expression of γH2AX suggests damage to DNA in MGO-treated cells. A decrease in HDAC1/2 expression, consistent with the increase in acetylated histone H4 levels, and an inhibition of the expression of TET (TET1, TET2) proteins was observed in MGO-treated cells. These results suggest that MGO may also disrupt epigenetic homeostasis mechanisms, offering further insight into the pathways through which MGO causes cellular damage in intestinal cells.
A Macrophage-Derived 7-Gene Signature Predicts Prognosis and Therapeutic Response in Hepatocellular Carcinoma.
Li X, Li Z, Zhai J … +1 more , Zou B
IUBMB Life · 2025 Dec · PMID 41355397 · Full text
This study aimed to identify a novel prognostic signature derived from an EGFR Tyrosine kinase inhibitors (TKI-resistant) macrophage subpopulation and to evaluate its clinical and therapeutic relevance in HCC. We utilize...
This study aimed to identify a novel prognostic signature derived from an EGFR Tyrosine kinase inhibitors (TKI-resistant) macrophage subpopulation and to evaluate its clinical and therapeutic relevance in HCC. We utilized single-cell RNA sequencing data from HCC patients. An EGFR-TKI resistance score was calculated across all cell types. Macrophages, which exhibited the highest resistance score, were sub-clustered to identify the most resistant subpopulation. Marker genes from this sub-cluster were intersected with differentially expressed genes (DEGs) from the TCGA-LIHC cohort. A robust prognostic model was constructed. The model's performance was rigorously validated, and the signature was further characterized through multi-omics analysis and its correlation with immune checkpoint blockade (ICB) response and drug sensitivity. scRNA-seq analysis unequivocally identified macrophages as possessing the highest EGFR-TKI resistance score. We identified seven key prognostic genes: SLC41A3, DCAF13, PPM1G, NDC80, FAM83D, FUCA2, and UQCRH. A risk model built on these seven genes effectively stratified patients into high- and low-risk groups with significantly different overall survival (OS) in the TCGA cohort, a finding successfully validated in the independent GSE76427 cohort. A clinical nomogram integrating the risk score demonstrated excellent predictive accuracy, with AUC values for 1-, 3-, and 5-year OS of 0.816, 0.781, and 0.799, respectively. The low-risk group was associated with a favorable immune-infiltrated phenotype and was predicted to be more sensitive to immunotherapy. Conversely, the high-risk group exhibited distinct genomic features and was predicted to be more sensitive to specific targeted agents, including Navitoclax and Sorafenib. We identified and validated a novel 7-gene prognostic signature derived from a subpopulation of EGFR-TKI-resistant macrophages. This signature accurately predicts patient survival, offers insights into the molecular mechanisms of therapy resistance in HCC, and provides a promising tool for improved patient stratification and the development of personalized treatment strategies.
Oncogenic Role of PTPN14 in Pancreatic Cancer Through β-Catenin/NF-κB Pathway Activation.
Luo D, Luo X, Qian S … +1 more , Liu J
IUBMB Life · 2025 Nov · PMID 41255096 · Publisher ↗
Pancreatic cancer (PC) is one of the deadliest malignancies due to early metastasis, therapy resistance, and a highly immunosuppressive microenvironment. Although oncogenic mutations such as KRAS and TP53 are well charac...
Pancreatic cancer (PC) is one of the deadliest malignancies due to early metastasis, therapy resistance, and a highly immunosuppressive microenvironment. Although oncogenic mutations such as KRAS and TP53 are well characterized, the role of protein tyrosine phosphatase non-receptor type 14 (PTPN14)-a Hippo-pathway regulator implicated in other cancers-remains unclear in PC. PTPN14 expression was analyzed in PC tissues and cell lines using immunohistochemistry and western blotting. Functional effects of PTPN14 knockdown or overexpression on proliferation, apoptosis, migration, and invasion were evaluated in vitro using CCK-8, flow cytometry, wound healing, and Transwell assays. Molecular mechanisms were explored via western blotting, immunofluorescence, and rescue experiments focusing on β-catenin and NF-κB signaling. In vivo, a xenograft mouse model assessed tumor growth, histopathology, apoptosis (TUNEL), Ki67 expression, and serum cytokine levels (ELISA). PTPN14 was markedly upregulated in PC tissues and cell lines. Silencing PTPN14 significantly inhibited cell proliferation, migration, and invasion, while enhancing apoptosis in vitro. Mechanistically, PTPN14 activated β-catenin and NF-κB signaling, promoting β-catenin nuclear translocation and p65 phosphorylation, with increased IL-6, TNF-α, and IL-1β secretion. In vivo, PTPN14 knockdown suppressed xenograft tumor growth, reduced Ki67 expression, enhanced apoptosis, and lowered serum pro-inflammatory cytokines. PTPN14 drives PC progression by co-activating β-catenin and NF-κB pathways and promoting a pro-tumor inflammatory milieu. These findings highlight PTPN14 as a promising therapeutic target to inhibit PC aggressiveness and inflammation-driven tumor progression.
Silent Guardians Gone Rogue: The Role of PIWI and piRNA in Malignant Transformation.
Lalruatfela A, Biswal P, Behera SK … +4 more , Biswal S, Dash JJ, Behera DK, Mallick B
IUBMB Life · 2025 Nov · PMID 41239887 · Publisher ↗
Malignant transformation is not merely the consequence of stochastic genetic mutations but rather a convergence of complex interplay between genetic, epigenetic, and environmental factors that collectively reprogram norm...
Malignant transformation is not merely the consequence of stochastic genetic mutations but rather a convergence of complex interplay between genetic, epigenetic, and environmental factors that collectively reprogram normal cells into cancerous ones. Central to these processes is the loss of tumor suppressor genes, activation of oncogenes, chromosomal instability, and widespread epigenetic remodeling. A pivotal aspect of this transformation involves the contribution of ncRNAs that have been recurrently implicated in malignant transformation. While much attention is directed toward miRNAs, circRNAs, and lncRNAs, piRNAs have remained comparatively overlooked in cancer biology. This is despite a growing body of evidence implicating piRNAs in regulating tumorigenic pathways, genomic stability, and epigenetic gene silencing. Our review explores the emerging role of the piRNAs and their regulatory protein PIWI in modulating key malignant features, including hyperproliferation, EMT, tumor evasion, migration, angiogenesis, and others. We also examine how this axis influences the initiation and progression of cancer, highlighting its potential to reshape established paradigms in cancer studies.
G-Patch Domain-Containing Protein 2, Transcriptionally Activated by YY1, Facilitates the Progression of Hepatocellular Carcinoma by Boosting SNAI2 Expression.
Bie B, Bai H, Li Y … +2 more , Wang G, Sun J
IUBMB Life · 2025 Nov · PMID 41236130 · Publisher ↗
G-patch domain-containing protein 2 (GPATCH2), a member of the G-patch domain-containing family, has been implicated in tumor cell growth, but the link between GPATCH2 and hepatocellular carcinoma (HCC) remains uncertain...
G-patch domain-containing protein 2 (GPATCH2), a member of the G-patch domain-containing family, has been implicated in tumor cell growth, but the link between GPATCH2 and hepatocellular carcinoma (HCC) remains uncertain. In the current study, comprehensive bioinformatics analysis revealed that GPATCH2 was markedly upregulated in HCC and positively correlated with aggressive clinicopathological features, including histologic grade, AFP, albumin level, and adjacent hepatic tissue inflammation, as well as miserable outcomes in HCC. GPATCH2 also has certain diagnostic value for HCC, histologic grade, and 1-, 3-, and 5-year survival outcomes. Functionally, loss-of-function experiments disclosed that silencing GPATCH2 suppressed HCC cell proliferation, migration, invasion, and xenograft tumor growth in the subcutaneous mouse model. Silencing GPATCH2 also resulted in an increase in the expression level of CDH1, while causing a decrease in the expression levels of FN1, TWIST1, SNAI1, and SNAI2. Rescue experiments further confirmed SNAI2 as a critical downstream effector mediating GPATCH2-driven oncogenic activity in HCC. Mechanistically, GPATCH2 was uncovered to be transcriptionally activated by the transcription factor Yin Yang 1 (YY1), and can mediate the role of YY1 in promoting HCC progression and elevating SNAI2 expression. Taken together, GPATCH2 is a YY1-regulated oncogenic driver that promotes HCC advancement through SNAI2, highlighting its potential as a diagnostic, prognostic, and therapeutic target for HCC.
MTFR1 Promotes Proliferation and Metastasis of Triple-Negative Breast Cancer by Regulating Mitochondrial Metabolism.
Zhu Z, Wang J, Liu J … +1 more , Sun G
IUBMB Life · 2025 Nov · PMID 41222164 · Publisher ↗
Mitochondria, as the center of cellular energy metabolism, play multiple key roles in the progression of triple-negative breast cancer (TNBC). Mitochondrial fission regulator 1 (MTFR1) is a mitochondrial regulatory facto...
Mitochondria, as the center of cellular energy metabolism, play multiple key roles in the progression of triple-negative breast cancer (TNBC). Mitochondrial fission regulator 1 (MTFR1) is a mitochondrial regulatory factor that plays a part in regulating mitochondrial fission and cell development. It is still unknown how MTFR1 functions in TNBC. We discovered MTFR1 to be a crucial gene in TNBC with clinical diagnostic value using database mining analysis. The effects of MTFR1 on TNBC cell proliferation, migration, invasion, and mitochondrial function were determined using the Cell Counting Kit-8, wound healing, and Transwell assays. Nude mouse models were established to explore the impact of MTFR1 on TNBC tumor growth and metastasis. Additionally, western blot and transcriptome sequencing (RNA-seq) were used to investigate the mechanism of MTFR1's involvement in TNBC progression. We used database extraction, WGCNA, Cox regression, and ROC (receiver operating characteristic) curve analysis to identify and confirm MTFR1 as a critical gene in TNBC. In TNBC patients, high MTFR1 expression is related to poor prognosis and diagnostic value. Knockdown of MTFR1 inhibits the proliferation and metastasis of TNBC cells and tumor bodies, affecting mitochondrial function. MTFR1 knockdown inhibits the growth, metastasis, and mitochondrial function of TNBC cells and tumors. Furthermore, transcriptome sequencing and western blot experiments confirmed that MTFR1 knockdown inhibits the activation of the NF-κB signaling pathway. In this study, we report for the first time that MTFR1 is a critical gene upregulated in TNBC. MTFR1 is an oncogene in TNBC and is involved in cell growth, migration, and mitochondrial function, and promotes TNBC progression through the NF-κB signaling pathway. Therefore, targeting MTFR1 may be a promising therapeutic target for TNBC patients.
MIA3 in Coronary Artery Disease (CAD): An In-Depth Review of Its Role in Vascular Smooth Muscle Cell (VSMC) Homeostasis, Pathogenesis, and Its Therapeutic Potential.
Ali YT, Ravindran A, Eichelmann L … +2 more , Odenthal N, Aherrahrou R
IUBMB Life · 2025 Nov · PMID 41216662 · Publisher ↗
A significant portion of fatalities from coronary artery disease (CAD) has been attributed to be primarily triggered by atherosclerosis. The melanoma inhibitory activity protein-3 (MIA3) gene has been found to be a key r...
A significant portion of fatalities from coronary artery disease (CAD) has been attributed to be primarily triggered by atherosclerosis. The melanoma inhibitory activity protein-3 (MIA3) gene has been found to be a key regulator for plaque stability in coronary artery atherosclerosis. Recent advances have unveiled the role of this gene in the formation of MIA3 protein, via which it potentially regulates the homeostatic circuit of various molecular proteins inside the cell and provides a safety profile to heart patients. Understanding how this gene exists, functions, signals, and can be targeted is therefore crucial to tackle the challenges in the field of cardiology. In this review, we have elaborated on its role in various cellular processes and several reported diseases to develop a holistic insight into the function of this gene. We have shown how this gene contributes to the budding of vesicles from the endoplasmic reticulum and helps in the transport of apolipoproteins and collagen to the exterior of the cell. We shed light on its role in the pathogenesis of CAD and also explain its role in other diseases involving bone mineralization or collagen defects. We explore the MIA3 gene at both genetic and protein levels and elaborate on its evolutionary conservation across species. In this paper, we also dissect the signaling mechanisms of the MIA3 gene inside the cell involving several protein interactions to form the COPII complex and initiate the vesicular budding at the endoplasmic reticulum. We also discuss the various therapeutic options that can target the MIA3 signaling pathway in several diseases, with a particular emphasis on CAD.
Next-Generation Nanomaterials in Biology: From Tissue Regeneration to Targeted Cancer Therapy.
Barik D, Konkimalla VB
IUBMB Life · 2025 Nov · PMID 41211802 · Publisher ↗
The rapid advancement of nanotechnology has ushered in a new era of biomedical innovation, where nanomaterials serve as powerful tools at the interface of tissue regeneration and targeted cancer therapy. This review expl...
The rapid advancement of nanotechnology has ushered in a new era of biomedical innovation, where nanomaterials serve as powerful tools at the interface of tissue regeneration and targeted cancer therapy. This review explores the dual roles of nanomaterials in modulating biological responses, emphasizing their programmable and multifunctional nature. In tissue engineering, nanostructured scaffolds and cell-instructive surfaces recreate extracellular matrix cues, guiding stem cell behavior, promoting regeneration, and enabling organ-specific repair. Concurrently, in oncology, smart nanocarriers exploit tumor microenvironmental triggers-such as pH, redox gradients, or hypoxia-for precise drug delivery, reducing off-target effects and enhancing therapeutic outcomes. Next-generation platforms achieve dynamic control over cellular processes by integrating stimuli-responsive designs, immune modulation strategies, and mechano-sensitive systems. Furthermore, the convergence of regenerative and oncologic pathways-through shared signaling cascades, immune responses, and stem cell dynamics-demands a careful balance in nanoparticle programming to prevent unintended activation of malignant pathways. The review also highlights future directions, including intelligent, modular nanomaterials that synergize therapeutic, regenerative, and diagnostic capabilities. Collectively, these insights illuminate a path toward precision nanomedicine, where context-aware materials actively orchestrate healing or destruction with minimal collateral damage, transforming the future of personalized healthcare.
Integrated Multiomics Analysis and Mendelian Randomization Identify SIRT1 as a Pivotal Aging-Associated Gene in Meningioma.
Du G, Xu D, Sun J … +5 more , Che S, Ma J, Lan X, Wang J, Yan Z
IUBMB Life · 2025 Nov · PMID 41208649 · Full text
Meningiomas (MGMs) are the most prevalent benign intracranial tumors in adults, with incidence markedly increasing with age, underscoring the need to explore aging-associated molecular mechanisms. In this study, we integ...
Meningiomas (MGMs) are the most prevalent benign intracranial tumors in adults, with incidence markedly increasing with age, underscoring the need to explore aging-associated molecular mechanisms. In this study, we integrated transcriptomic datasets (GSE43290, GSE54934, GSE77259, and GSE183655) from the GEO database and aging-related genes (ARGs) from the Human Aging Genomic Resources to identify key genes implicated in MGM. We screened differentially expressed ARGs (ARG-DEGs) and conducted GO and KEGG pathway enrichment analyses, revealing significant involvement in cancer-related processes, viral infection pathways, and the FoxO signaling pathway. Using LASSO, SVM, CytoHubba-MCC, and MCODE algorithms, we identified two hub ARGs, SIRT1 and CEBPB. Immune infiltration analysis via ssGSEA indicated notable alterations in B cells, neutrophils, helper T cells, and regulatory T cells between MGM and healthy tissues, all closely associated with the hub genes. Furthermore, construction of a miRNA-TF-mRNA regulatory network highlighted the complex upstream regulation of these genes. Mendelian randomization analysis supported a potential causal relationship between SIRT1 and MGM development. Single-cell RNA sequencing data further confirmed heterogeneous expression of SIRT1 across key cell populations within MGM, brain-tumor interface, and dura mater tissues. These findings were validated through qRT-PCR and Western blot analyses, which demonstrated significant differences in SIRT1 expression at both the transcript and protein levels. Collectively, our study reveals that aging and immune dysregulation contribute to MGM pathogenesis and highlights SIRT1, in particular, as a potential diagnostic biomarker and therapeutic target, offering new insights into age-related mechanisms underlying MGM.
4-Methylumbelliferone Sensitizes Breast Cancer Spheroids to Chemotherapeutic Treatment With Epirubicin: New Perspectives for Pharmacological Repositioning.
Vitale DL, Icardi A, Rosales P … +3 more , Morán C, Sevic I, Alaniz LD
IUBMB Life · 2025 Nov · PMID 41204774 · Publisher ↗
Chemoresistance remains a significant hurdle in breast cancer treatment. To address this, we explored the therapeutic potential of combining epirubicin, an anthracycline commonly associated with the development of resist...
Chemoresistance remains a significant hurdle in breast cancer treatment. To address this, we explored the therapeutic potential of combining epirubicin, an anthracycline commonly associated with the development of resistance in cancer cells and with known cytotoxic effects, with 4-methylumbelliferone, a plant-derived coumarin. Our results demonstrated a coactive enhancement of epirubicin efficacy when this combination was applied to 3D breast cancer models, irrespective of molecular subtype. Mechanistically, 4-methylumbelliferone inhibits synthesis of hyaluronan, a key component of the tumor microenvironment that promotes tumor growth and metastasis. By disrupting hyaluronan production, this compound facilitated drug penetration into tumor spheroids and reduced the expression of drug efflux pumps, thereby increasing intracellular drug accumulation. Consequently, the combined treatment led to a significant reduction in cell viability and promotion of cell death. Our findings suggest that targeting hyaluronan metabolism in conjunction with conventional chemotherapy offers a promising strategy to overcome drug resistance in breast cancer. This drug repositioning approach not only improves treatment efficacy but also highlights the potential of targeting the tumor microenvironment to enhance cancer therapy. Further studies are warranted to elucidate the underlying mechanisms and to evaluate the clinical translation of this combination therapy.
Critical Contribution of Various Signaling Pathways in the Development of Drug Resistance in Colorectal Cancer: An Update.
Molavand M, Majidinia M, Yousefi B
IUBMB Life · 2025 Nov · PMID 41174903 · Publisher ↗
Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide, with drug resistance being a major challenge in limiting the available treatment options. This review focuses on the signaling pathw...
Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide, with drug resistance being a major challenge in limiting the available treatment options. This review focuses on the signaling pathways (Hedgehog, Hippo, Notch, Wnt/β-catenin, PI3K/Akt, and MAPK/ERK pathways) that are implicated in the development of drug resistance mechanisms in CRC, such as DNA repair systems, tumor microenvironments, autophagy, metabolic reprogramming, evasion of apoptosis, and efflux pumps. Furthermore, recent advancements in targeted and combinatorial diagnostic-therapeutic approaches are highlighted. This review delineates the significance of signaling cascades and their clinical relevance, offering novel perspectives on the formulation of therapeutic strategies to mitigate drug resistance. In light of the increasing prevalence of drug-resistant CRC and the lack of effective solutions, it addresses the persistent demand for improved therapeutic modalities and provides a comprehensive framework for forthcoming research in this domain.
CDCA4/SERTAD1/E2F1 Facilitates Lung Adenocarcinoma Progression by Inhibiting PINK1/Parkin-Mediated Mitophagy.
Tan J, Wang J, Zhang W … +1 more , Zhang C
IUBMB Life · 2025 Oct · PMID 41137604 · Publisher ↗
Cell division cycle-associated protein 4 (CDCA4) has the potential to indicate lung adenocarcinoma (LUAD) development, but its regulatory role in mitophagy remains unclear. This study aimed to elucidate the mitophagy reg...
Cell division cycle-associated protein 4 (CDCA4) has the potential to indicate lung adenocarcinoma (LUAD) development, but its regulatory role in mitophagy remains unclear. This study aimed to elucidate the mitophagy regulation and therapeutic implications of CDCA4 in LUAD. CDCA4 expression was significantly elevated in LUAD clinical specimens versus paracancerous tissues and inversely correlated with mitophagy activity. Lentiviral vectors were employed to manipulate established LUAD cells, followed by treatment with chloroquine (CQ; lysosomal inhibitor) and rapamycin (autophagy inducer) in CDCA4-silenced cells. CDCA4 knockdown elevated total and mitochondrial superoxide levels, disrupted mitochondrial membrane potential, activated the PINK1/Parkin pathway, enhanced LC3-II conversion, and degraded mitochondrial membrane proteins, collectively promoting mitophagy. Silencing CDCA4 suppressed malignant phenotypes (proliferation/migration), effects reversed by CQ but exacerbated by rapamycin. Mechanistically, CDCA4 interacted with SERTAD1 and E2F1 and stabilized these proteins. The promotion of mitophagy by CDCA4 silencing was impaired by the overexpression of SERTAD1 and E2F1. LUAD cells silencing CDCA4 were injected into immunodeficient mice for in vivo verification. CDCA4-silenced xenografts exhibited suppressed tumor growth, increased apoptosis, and elevated mitophagy-related markers. This study identifies the CDCA4/SERTAD1/E2F1 complex as a pivotal mitophagy-inhibitory hub in LUAD, proposing this axis as a novel predictive and therapeutic target.
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