Molecular And Cellular Biochemistry[JOURNAL]
Sun
200 papers
Transforming growth factor-β3 attenuates septic cardiomyopathy by reversing cardiomyocyte metabolic reprogramming through Smad7 signaling.
Zhang H, Xu J, Xu B … +1 more , Shang X
Mol Cell Biochem · 2026 Mar · PMID 41483124 · Full text
Septic cardiomyopathy (SCM) exhibits over 70% mortality, primarily attributed to cardiomyocyte metabolic reprogramming shifting from oxidative phosphorylation (OXPHOS) to glycolysis. Although transforming growth factor-β...
Septic cardiomyopathy (SCM) exhibits over 70% mortality, primarily attributed to cardiomyocyte metabolic reprogramming shifting from oxidative phosphorylation (OXPHOS) to glycolysis. Although transforming growth factor-β3(TGF-β3) modulates energy metabolism in other tissues, its function in SCM pathogenesis remains unexplored. In vivo, cecal ligation puncture (CLP) rat models received myocardial injections of TGF-β3-overexpressing or interfering adenovirus. Myocardial injury through histopathology (H&E) and apoptosis (TUNEL), and mitochondrial ultrastructure via transmission electron microscopy (TEM). In vitro, primary cardiomyocytes treated with lipopolysaccharide (LPS) were transfected with TGF-β3 overexpression plasmid, with metabolic analyzed using Seahorse XF technology (extracellular acidification rate, ECAR; oxygen consumption rate, OCR). Molecular mechanisms were investigated via Western blotting and co-immunoprecipitation (Co-IP) targeting TGF-β3/Smad7/SKP1 signaling. TGF-β3 was significantly downregulated in SCM. Its overexpression attenuated myocardial injury and apoptosis, improved mitochondrial integrity, and reversed metabolic reprogramming by reducing glycolysis while enhancing OXPHOS. Mechanistically, TGF-β3 promoted Smad7 phosphorylation to inhibit Smad2/3 activation and suppressed SKP1 expression to reduce Smad7 ubiquitination, as confirmed by Co-IP. TGF-β3 confers cardioprotection in SCM by reversing metabolic reprogramming through dual regulation of Smad7: enhancing phosphorylation to block Smad2/3 signaling and inhibiting SKP1-mediated ubiquitination to stabilize Smad7. This newly identified TGF-β3/Smad7 axis represents a promising therapeutic target for SCM.
Molecular mechanisms of PCSK9 in cardiology: therapeutic implications and clinical impacts on the cardiorenal axis.
Kaur S, Panjwani D, Singh S … +4 more , Banerjee S, Wadehra S, Kaur A, Singh TG
Mol Cell Biochem · 2026 Mar · PMID 41483123 · Publisher ↗
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in the molecular pathophysiology of the cardiorenal axis by facilitating the degradation of LDL receptors, which results in increased LDL cholest...
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in the molecular pathophysiology of the cardiorenal axis by facilitating the degradation of LDL receptors, which results in increased LDL cholesterol levels, inflammation, and fibrosis. PCSK9 is involved in activating various pathways, including NF-κB and the NLRP3 inflammasome, while simultaneously inhibiting PPAR and SIRT3. This dysregulation contributes to oxidative stress, apoptosis, and renal lipotoxicity through the impairment of megalin function. The resultant molecular processes lead to the secretion of proinflammatory cytokines such as IL-1β, IL-6, TNF-α, and NF-κB, which exacerbate fibrosis and tissue injury. The heightened activity of PCSK9 is associated with the accumulation of LDL in the kidneys, causing nephrotoxicity and dysfunction within the cardiorenal system. Notably, the inhibition or deficiency of PCSK9 has been shown to confer protective effects, mitigating inflammation, oxidative stress, and apoptosis in the cardiorenal axis. Consequently, targeting PCSK9 and its related pathways may pave the way for innovative therapeutic approaches aimed at reducing inflammation, oxidative stress, and apoptosis, thereby enhancing the clinical outcomes for individuals with cardiorenal dysfunction.
Nutritional modulation of metabolic signaling within the tumor microenvironment for cancer therapy.
Aghdam MM, Rezagholizadeh L, Fazaeli A … +2 more , Moradi A, Ojarudi M
Mol Cell Biochem · 2026 Mar · PMID 41483122 · Publisher ↗
The tumor microenvironment (TME) constitutes a complex ecosystem of cellular and non-cellular components. Together, these constituents exert a critical influence on cancer progression. A principal mechanism underlying th...
The tumor microenvironment (TME) constitutes a complex ecosystem of cellular and non-cellular components. Together, these constituents exert a critical influence on cancer progression. A principal mechanism underlying this influence is metabolic reprogramming, in which tumor cells alter glucose, amino acid, and lipid metabolism to promote growth, survival, and immune evasion. Metabolic adaptation is further regulated by nutrient-sensing pathways, including mammalian target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), and hypoxia-inducible factor (HIF), which often exhibit context-dependent and sometimes opposing functions in tumor and immune cells within the TME. Given this complexity, targeting metabolic vulnerabilities has become a promising therapeutic approach. In this context, nutritional interventions, such as caloric restriction, ketogenic diets, fasting-mimicking diets, protein or amino acid modulation, and lipid metabolism adjustments, aim to deprive tumors of essential nutrients, remodel the immunosuppressive TME, and increase cancer cell sensitivity to chemotherapy, radiotherapy, and immunotherapy. However, the efficacy of these interventions varies according to cancer type, oncogenic drivers, and immune contexture, and there is a risk of impairing anti-tumor immune function. Addressing these challenges will require personalized nutrition strategies that integrate tumor genetics, metabolic profiling, and the gut microbiome, together with technological advances for real-time monitoring. Progress in this area depends on a deeper mechanistic understanding of nutrient-immune interactions and the optimization of combination approaches for improved metabolic targeting in precision oncology. Accordingly, this review addresses a critical gap by synthesizing mechanistic and translational literature and outlining actionable priorities to advance nutritional modulation from preclinical research to clinical application.
The "Cold Tumor" to "Hot Tumor" transformation strategy for triple-negative breast cancer: from mechanism to clinical translation.
Wang H, Li F, Hao P … +1 more , Mei Y
Mol Cell Biochem · 2026 Mar · PMID 41483121 · Publisher ↗
Triple-negative breast cancer (TNBC) has become a clinical challenge due to its high invasiveness, the lack of clear therapeutic targets, and the limitations of existing treatment methods. It is worth noting that althoug...
Triple-negative breast cancer (TNBC) has become a clinical challenge due to its high invasiveness, the lack of clear therapeutic targets, and the limitations of existing treatment methods. It is worth noting that although TNBC is the subtype with the highest immune infiltration and the best response to immune checkpoint inhibitor (ICI), the response rate of ICI monotherapy for TNBC is only 15-20%, which could be partially explained by its “cold tumor” characteristics, not allowing an adequate immune response activation to be primed. Although the pathological complete response rate (pCR) of ICI combined with chemotherapy in trials such as Keynote 522 exceeded 50%. However, the core characteristics of “cold tumors”—including insufficient immune cell infiltration (such as cytotoxic T lymphocyte (CTL) deficiency) and a strong immunosuppressive microenvironment—remain key factors affecting further improvement of therapeutic efficacy. Therefore, transforming “cold tumors” into “hot tumors” (i.e., immune inflammatory tumors) is a key scientific issue for enhancing the efficacy of TNBC immunotherapy.
Intratumoural microbial metabolites in breast cancer: a longitudinal study on association with metastatic progression.
Seenivasan SN, Vasudevan SA, Raghupathy AK … +8 more , Rajan F, Selvan E, Sharma SM, Muthusamy RK, Paramasivam L, Seethalakshmi SP, Yogeswaran S, Velmurugan G
Mol Cell Biochem · 2026 Feb · PMID 41432892 · Publisher ↗
Delayed diagnosis and metastasis remain major challenges in breast cancer. While the gut microbiome’s influence on tumour progression is established, the presence and role of intratumoural microbial metabolites in breast...
Delayed diagnosis and metastasis remain major challenges in breast cancer. While the gut microbiome’s influence on tumour progression is established, the presence and role of intratumoural microbial metabolites in breast cancer and their association with metastasis remain unexplored. Paired tumour and adjacent tissues were collected from 50 breast cancer patients at baseline. Patients were followed for five years; 10 who developed distant metastasis were classified as pre-metastatic, and 10 who remained disease-free formed the non-metastatic group. Untargeted LC–MS/MS-based metabolomics was performed to profile host and microbial metabolites. Multivariate analysis and pathway enrichment were used to identify discriminatory signatures. Elevated levels of carnitine, indole, tryptophan-derived metabolites, ceramides and polyamines were observed in tumour tissues on comparison with adjacent tissues. Interestingly, these metabolites were downregulated in tumour tissues of patients who progressed for metastasis (pre-metastatic) with increase in N-methylhistamine and taurolithocholic acid sulfate, suggesting metabolic reprogramming during metastatic priming. Baseline host–microbial metabolic disruptions in breast tumours are linked to future metastasis, with metabolites like indoles, bile acids, and polyamines showing promise as early biomarkers and therapeutic targets in precision oncology.
ALKBH5 promotes gastric cancer angiogenesis by stabilizing LncRNA PVT1 and VEGFA RNAs via m6A demethylation.
Geng Q, Li D, Zhu W … +5 more , Qi C, Wang T, Yang H, Shu Y, Jiang H
Mol Cell Biochem · 2026 Feb · PMID 41428170 · Publisher ↗
AlkB homolog 5 (ALKBH5) has been implicated in tumor progression, however, its specific role in angiogenesis in gastric cancer (GC) and the underlying mechanisms remain poorly understood. Messenger RNA (mRNA) expression...
AlkB homolog 5 (ALKBH5) has been implicated in tumor progression, however, its specific role in angiogenesis in gastric cancer (GC) and the underlying mechanisms remain poorly understood. Messenger RNA (mRNA) expression levels of vascular endothelial growth factor A (VEGFA), ALKBH5, and long non-coding RNA PVT1 (lncRNA PVT1) in GC and paracancerous tissues were measured by quantitative real-time polymerase chain reaction (qRT-PCR). RNA sequencing (RNA-seq) was employed to identify downstream effectors of lncRNA PVT1. The effects of ALKBH5 and lncRNA PVT1 on angiogenesis were examined in vitro and in vivo. The impact of ALKBH5 on the stability of lncRNA PVT1 and VEGFA RNAs was evaluated by mRNA stability assays, and interactions between ALKBH5 and these RNAs were validated using methylated RNA immunoprecipitation (MeRIP) assay. A significant positive correlation was observed among ALKBH5, lncRNA PVT1, and VEGFA expression in both The Cancer Genome Atlas (TCGA) GC database and sixty GC tissue samples. ALKBH5 and lncRNA PVT1 enhanced angiogenesis in AGS and HS746T cells both in vitro and in vivo. RNA-seq revealed that lncRNA PVT1 upregulated VEGFA mainly through the IL17RA/STAT3 signaling pathway. Additionally, ALKBH5 was found to stabilize both lncRNA PVT1 and VEGFA RNAs. MeRIP assays confirmed the direct binding of ALKBH5 to specific sites on lncRNA PVT1 and VEGFA RNAs. In conclusion, ALKBH5 promotes GC angiogenesis primarily through its m6A demethylase activity on targets such as lncRNA PVT1, which regulates VEGFA expression by modulating IL17RA/STAT3 signaling axis. ALKBH5 may serve as a promising biomarker and therapeutic target in GC.
Correction: Updated insights on ASK1 signaling: mechanisms, regulation, and therapeutic potential in diseases.
Thakur D, Nandi A, Gaur YK … +4 more , Karthikeyan C, Waiker DK, Das Gupta G, Sharma K
Mol Cell Biochem · 2026 Mar · PMID 41417422 · Publisher ↗
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APOBEC3B-driven mutations negatively regulated by P53 promote tumor progression and immunosuppressive microenvironment in prostate cancer.
Guo Y, Yu H, Li X … +11 more , Liu L, He J, Wang X, Zhang H, Zhang Q, Fu J, Gu R, Li H, Xu D, Liu Q, Cang SD
Mol Cell Biochem · 2026 Feb · PMID 41385179 · Full text
APOBEC3B (A3B), a key cytosine deaminase, plays a multifaceted role in the malignant progression of various cancers. However, the precise role of A3B in prostate cancer (PCa) remains largely elusive. This study aimed to...
APOBEC3B (A3B), a key cytosine deaminase, plays a multifaceted role in the malignant progression of various cancers. However, the precise role of A3B in prostate cancer (PCa) remains largely elusive. This study aimed to investigate the functional significance of A3B in PCa and evaluate its potential as a therapeutic target. We first demonstrated that A3B is significant upregulated in PCa tissues and positively correlated with higher Gleason scores, poorer prognostic outcomes, and an increased frequency of cytosine deamination-induced mutagenesis. Functional enrichment analysis further revealed that A3B is closely associated with biological processes such as "cell cycle regulation" and "epithelial-mesenchymal transition (EMT)." To validate the biological role of A3B in PCa cells, we conducted a series of in vitro assays, including CCK-8, EdU, colony formation, and transwell migration/invasion. Notably, A3B knockdown suppressed the proliferation of PC-3 cells and reduced their migratory and invasive capabilities by modulating EMT. Conversely, A3B overexpression enhanced these effects in 22RV1 cells. In vivo tumor xenograft experiments further supported our findings, confirming that A3B promotes the growth of PCa cells in mice. Mechanistically, p53 was identified as a suppressor of A3B expression, thereby alleviating genomic instability. Additionally, a combination of multiplex immunofluorescence (mfIHC) and qRT-PCR analyses validated that elevated A3B expression correlates with increased infiltration of immunosuppressive cells, including regulatory T cells (Tregs), CD8 + PD-1 + T cells, and CD163 + macrophages. This infiltration may be mediated by cytokines and chemokines. Collectively, these findings suggest that A3B holds potential as a novel prognostic biomarker and immunotherapeutic target for PCa.
Senescent cell clearance suppresses post-radiotherapy glioblastoma recurrence via the IL-6/JAK2/STAT3 pathway.
Nie P, Zhou J, Zhang J … +2 more , Chen J, Zhang J
Mol Cell Biochem · 2026 Feb · PMID 41385178 · Publisher ↗
Glioblastoma (GBM), the most aggressive primary brain tumor in adults, invariably recurs post-radiotherapy despite being a standard treatment. Tumor relapse within irradiated regions is characterized by heightened therap...
Glioblastoma (GBM), the most aggressive primary brain tumor in adults, invariably recurs post-radiotherapy despite being a standard treatment. Tumor relapse within irradiated regions is characterized by heightened therapeutic resistance, which we mechanistically link to radiotherapy-induced remodeling of the tumor microenvironment. Here, we demonstrate that ionizing radiation triggers profound senescence in astrocytes, evidenced by β-galactosidase activity, G1 cell cycle arrest, p21 upregulation, and Lamin B1 downregulation. Persistent senescence signatures were observed in GFAP⁺ cells of irradiated mouse brains for ≥ 49 days. Conditioned medium from senescent astrocytes markedly enhanced proliferation, migration, and invasion of GBM cells. Intracranial U251 xenografts in pre-irradiated mice exhibited accelerated tumor growth and reduced survival, phenotypes rescued by the senolytic agent ABT-263. Transcriptomic profiling identified IL6 as the predominant senescence-associated secretory phenotype (SASP) factor elevated in irradiated astrocytes. Senescent conditioned medium activated JAK2/STAT3 signaling in GBM cells, effects abrogated by ABT-263 or tocilizumab (IL6R neutralizing antibody). Functional assays confirmed that IL6 blockade suppressed GBM aggressiveness, mirroring senolytic treatment outcomes. Our findings establish radiation-induced astrocyte senescence as a critical driver of GBM recurrence through IL6-mediated JAK2/STAT3 activation, nominating senolytics as promising adjuvants to improve radiotherapy efficacy.
Clocking the damage: circadian rhythm, redox homeostasis and genome integrity in cancer.
Ganesh JM, Singh P, Murali R … +3 more , Chandramoorthy HC, Perumalsamy LR, Gandhirajan RK
Mol Cell Biochem · 2026 Mar · PMID 41364289 · Publisher ↗
Circadian rhythms are inherent biological cycles that govern vital physiological processes, aligning with external signals such as light and food consumption. These rhythms, which originated over 2.5 billion years ago as...
Circadian rhythms are inherent biological cycles that govern vital physiological processes, aligning with external signals such as light and food consumption. These rhythms, which originated over 2.5 billion years ago as a defense against oxidative stress, are essential for maintaining genomic stability by regulating DNA repair pathways, oxidative stress responses, and cell cycle regulation. Alterations in circadian rhythms are increasingly attributed to modern lifestyle practices, including irregular sleep schedules, prolonged exposure to artificial light, and shift work. These disturbances are closely linked to increased oxidative damage and genomic instability, both of which are essential for the development of cancer. There is growing evidence linking circadian misalignment to cancer, and the International Agency for Research on Cancer (IARC) has categorized shift employment that disturbs circadian rhythms as a potential carcinogen. Sleep deprivation intensifies this imbalance, resulting in heightened DNA damage and compromised repair processes. This disturbance is especially alarming in younger individuals, as chronic circadian misalignment may contribute to increasing prevalence of early-onset cancers, including hormone-related malignancies. This review examines the impact of oxidative stress-induced instability and the function of circadian rhythms in mitigating these effects. It underscores the critical influence of sleep deprivation on circadian misalignment and its associated cancer risk implications. Comprehending these relationships is essential for formulating preventive strategies and enhancing cancer treatments, thereby aligning therapeutic interventions with the body's intrinsic biological clock. Mitigating lifestyle-induced circadian disturbances may be crucial in alleviating the increasing incidence of early-onset malignancies in younger adults.
M1 macrophage exosomes inhibit lung adenocarcinoma growth by up-regulating KLF6 via the reduction of ALKBH5-mediated KLF6 demethylation.
Gou J, Jia T, Song S … +2 more , He J, Zhao D
Mol Cell Biochem · 2026 Feb · PMID 41348384 · Publisher ↗
M1 macrophage exosomes (M1-Exos) have been shown to play a significant role in regulating Lung adenocarcinoma (LUAD) progression. Krüppel-Like Factor 6 (KLF6) is a widely expressed nuclear transcriptional regulator invol...
M1 macrophage exosomes (M1-Exos) have been shown to play a significant role in regulating Lung adenocarcinoma (LUAD) progression. Krüppel-Like Factor 6 (KLF6) is a widely expressed nuclear transcriptional regulator involving in various key cellular processes and functions as a tumor suppressor. Here, this study aimed to investigate the role of KLF6 in LUAD and whether M1-Exos function in LUAD by KLF6. Levels of mRNA and protein were detected using qRT-PCR and western blotting. Exosomes were isolated from M1 macrophages and co-cultured with LUAD cell lines for functional analysis. In vitro analyses were conducted using 5-ethynyl-2'-deoxyuridine assay, flow cytometry and transwell assay. The N6-methyladenosine (m6A) modification profile was analyzed using the methylated RNA immunoprecipitation assay and the interaction was determined by RNA Immunoprecipitation assay. The murine model was established for in vivo analysis. M1 macrophage exosomes suppressed LUAD cell proliferation, migration and invasion. Further analyses showed that KLF6 was packaged in M1 macrophage exosomes and could be transferred into LUAD cells. Functionally, the incubation of KLF6-decreased M1 macrophage exosomes led to the enhancement of LUAD cell proliferation, migration and invasion. Mechanistically, alkylation repair homolog protein 5 (ALKBH5), an RNA m6A demethylase, could reduce KLF6 m6A modification and then broke the stabilization of KLF6 and decreased its expression in M1 macrophages and LUAD cells. Importantly, ALKBH5 reversed the anticancer effects of M1-Exo on LUAD cells. Moreover, the inhibition of LUAD tumor growth in vivo mediated by M1-Exo was also impeded by ALKBH5. In conclusion, M1 macrophage exosomes inhibited LUAD growth by reducing ALKBH5-mediated KLF6 demethylation.
The role of amino acid signaling in pathogenesis of chronic kidney disease.
Yan S, Zhang X, Bu R … +8 more , Li G, Wang Y, Cheng M, Chen Q, Wu Y, Zhang Y, Wang D, Wang T
Mol Cell Biochem · 2026 Mar · PMID 41348383 · Publisher ↗
Chronic kidney disease (CKD) is a comprehensive disease characterized by renal injury and decreased renal function, which can lead to increased cardiovascular and all cause mortality rates, seriously affecting the qualit...
Chronic kidney disease (CKD) is a comprehensive disease characterized by renal injury and decreased renal function, which can lead to increased cardiovascular and all cause mortality rates, seriously affecting the quality of life and lifespan of patients. At present, although renal function decline can be treated with hormone drugs and immunosuppressive drugs, these treatment methods have not shown any beneficial effects on preventing CKD from progressing to renal failure. Dietary intervention has always been one of the cornerstones of CKD treatment, and nephrologists use dietary intervention to reduce symptoms and metabolic complications of CKD and potentially prevent its progression. This review discusses the relationship between kidney disease and amino acids. In addition, we emphasize the regulatory role of amino acid signaling pathways in the progression of CKD, with a focus on causal relationships and potential mechanisms.
FABP3 deficiency exacerbates renal Randall plaque formation: insights from single-cell RNA transcriptomic analysis.
Iqbal MS, Duan X, Attia KA … +6 more , Nabi G, Peng K, Sardar N, Gu D, Zeng G, Al-Theyab NS
Mol Cell Biochem · 2026 Feb · PMID 41324865 · Publisher ↗
Randall’s plaque (RP) formation is a critical initiating process in calcium oxalate nephrolithiasis; however, the molecular mechanisms driving its pathogenesis remain incompletely understood. This study aimed to evaluate...
Randall’s plaque (RP) formation is a critical initiating process in calcium oxalate nephrolithiasis; however, the molecular mechanisms driving its pathogenesis remain incompletely understood. This study aimed to evaluate the role of fatty acid-binding protein 3 (FABP3), a key regulator of lipid metabolism and epithelial homeostasis, in RP development. We employed an integrative multi-omics approach incorporating single-cell RNA sequencing (scRNA-seq), quantitative real-time PCR (qPCR), immunohistochemistry (IHC), and pathway enrichment analyses on human renal papillary tissues from individuals with and without RP, alongside validation in a murine model. scRNA-seq revealed significant downregulation of FABP3 across 21 renal cell clusters within the RP microenvironment (mean expression: 0.0188). qPCR confirmed a tenfold reduction in FABP3 transcript levels in RP samples compared to controls (2^-ΔCt: 0.0714 vs. 0.6998; Cp values 24.05–25.31 vs. 20.97–22.77; p < 0.001), while IHC demonstrated parallel protein depletion in murine RP tissues. Functional enrichment analyses linked FABP3 deficiency to dysregulation of lipid metabolic pathways, including fatty acid transport and lipolysis, implicating these alterations in interstitial calcium deposition and plaque formation. In conclusion, this study identifies FABP3 as a central molecular determinant in RP pathogenesis, offering novel mechanistic insight and establishing FABP3 as a promising biomarker and therapeutic target for nephrolithiasis prevention.
Decoding the gut microbiota-mitochondrial-inflammasome axis in cardiovascular disease.
Chauhan R, Lidoo K, Jyoti U … +2 more , Singh TG, Devi S
Mol Cell Biochem · 2026 Mar · PMID 41324864 · Publisher ↗
The inter-disciplinary relationship between the gut microbiota, mitochondrial function, and inflammation activation represents a frontier in understanding Cardiovascular complications. This comprehensive review provides...
The inter-disciplinary relationship between the gut microbiota, mitochondrial function, and inflammation activation represents a frontier in understanding Cardiovascular complications. This comprehensive review provides a framework of the signalling networks that link these three biological systems and their collective impact on cardiovascular disease. The gut microbiota is a diverse ecological community comprising bacterial phyla, including Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria, which contribute to the functions of distal organs by producing bioactive metabolites. We systematically examined how microbial dysbiosis participates in inflammasome and mitochondrial-derived cardiovascular pathophysiology. This review also provides insight into various molecular pathways (TLR, PI3K/AKT, JAK/STAT, MAPK, TRPV, CREB, TXNIP, YAP, MyD88 and NLRP3) and therapeutic interventions targeting this axis, including gut microbiota modulation agents, mitochondrial-targeted antioxidants, and inflammasome inhibitors, offering mechanistic insights into their cardioprotective effects. Using current evidence and data from PubMed, Google Scholar, Web of Science, and ResearchGate, we provide a mechanistic understanding of the gut microbiota-mitochondria-inflammasome axis. This triad represents a critical target in cardiovascular health and warrants new diagnostic and therapeutic strategies.
Diagnostic potential of neutrophil extracellular traps in ulcerative colitis: a gene-based predictive model.
Liang H, Xu Y, Zhang X … +2 more , Han Z, Zhu J
Mol Cell Biochem · 2026 Feb · PMID 41324863 · Publisher ↗
BACKGROUND: Neutrophil extracellular traps (NETs), web-like structures released by neutrophils during the process NETosis, aiding in gut mucosal defense against microbial infections but potentially exacerbating inflammat...
BACKGROUND: Neutrophil extracellular traps (NETs), web-like structures released by neutrophils during the process NETosis, aiding in gut mucosal defense against microbial infections but potentially exacerbating inflammation and tissue damage. In Ulcerative Colitis (UC), NET formation is increased and may contribute to gut inflammation. However, the role of NETs in diagnosis of UC remains unclear. This study aims to identify NETs-related genes with diagnostic potential in UC and to develop a diagnostic predictive model based on these genes. METHOD: The transcriptome dataset of UC retrieved from the GEO database. Differential expression analysis and Gene Set Enrichment Analysis (GSEA) were performed on the training set using R software. The "CIBERSORT" algorithm was utilized to evaluate the immune cell infiltration in UC. Subsequently, differentially expressed NETs (DE-NETs) were identified by intersecting key module genes from Weighted Gene Co-Expression Network Analysis (WGCNA), NETs-related genes, and differentially expressed genes (DEGs). The diagnostic genes were identified through three machine learning algorithms (Least Absolute Shrink-age And Selection Operator (LASSO) algorithm, Random Forests (RF) and Support Vector Machine-Recursive Feature Elimination (SVM-RFE)). The results of the three algorithms were integrated to identify NETs-related diagnostic genes (NDGs). A clinical diagnostic predictive model was constructed based on NDGs, and its performance was assessed using calibration curves, Clinical Impact Curve (CIC), Decision Curve Analysis (DCA), and Receiver Operating Characteristic Curve (ROC) to evaluate its discrimination ability and clinical utility. Immunohistochemical (IHC) examination was performed on colon tissue from UC patients. Additionally, a DSS-induced UC mouse model was constructed, and NDG expression in mouse colon tissues was analyzed by qRT-PCR, Western-blot, and IHC. RESULTS: The UC group exhibits significant enrichment of immune-related pathways, including the IL-17 signaling pathway, cytokine-cytokine receptor interactions, and TNF signaling pathway, as well as enhanced infiltration of immune cells, as demonstrated by GSEA and immune infiltration analysis. Fourteen genes were identified through intersecting DEGs, key module genes in WGCNA, and NETs-related genes. The identification of IL-1β, MMP-9 and CXCR2 as NDGs was using three machine learning methods. The clinical diagnostic predictive model of UC based on NDGs was constructed, and the AUC value of the model was 0.9715 in the training set, and 0.9595 and 0.9597 in external validation sets, respectively. Significant positive correlations were found between NDGs and Mast cells, Neutrophils, resting NK cells, M1 Macrophages, Tregs and Eosinophils. IHC analysis of clinical samples shows high expression of NDGs in the colon of UC patients. A clinical-associated nomogram was constructed from the IHC scores of the clinical samples, exhibiting an AUC of 100%. In DSS-induced UC mice model, NDG expression was up-regulated compared to normal control mice. A mouse-associated nomogram was constructed based on IHC scores of mouse tissues, and the AUC was also 100%. CONCLUSIONS: We constructed a clinical diagnostic predictive model for UC based on IL-1β, MMP-9 and CXCR2 and validated the ability of NDGs to predict UC in the clinical patient and the animal model. The model has excellent diagnostic efficiency and can provide a new idea for clinical diagnosis of UC.
Deubiquitinase OTUD5 facilitates stiffness-induced hepatic stellate cell activation by stabilizing YAP.
Jia S, Niu Y, Nuernijiati N … +3 more , Zhang C, Li J, Tu K
Mol Cell Biochem · 2026 Feb · PMID 41324862 · Publisher ↗
Hepatic stellate cells (HSCs) activate and transdifferentiate into tumor-promoting myofibroblasts, which is an essential cause of colorectal liver metastasis. In addition to cytokines such as transforming growth factor-β...
Hepatic stellate cells (HSCs) activate and transdifferentiate into tumor-promoting myofibroblasts, which is an essential cause of colorectal liver metastasis. In addition to cytokines such as transforming growth factor-β, matrix stiffness is also a vital factor for promoting HSC activation. Our recent study reveals that OTU deubiquitinase 5 (OTUD5) promotes hepatocellular carcinoma progression, but its role and molecular mechanism in stiffness-induced HSC activation remain unclear. Polyacrylamide hydrogels with different composition ratios were used to simulate different matrix stiffnesses. Western blotting and immunofluorescence were performed to detect OTUD5, α-smooth muscle actin (α-SMA), connective tissue growth factor (CTGF), Yes-associated protein (YAP), cysteine-rich angiogenic inducer 61 (CYR61), HA, FLAG, ubiquitin (UB), and MYC levels. RT-qPCR was used to assess the expression of OTUD5, YAP, CYR61, and CTGF mRNA. The interaction between OTUD5 and YAP, as well as the YAP ubiquitination level, was determined using a co-immunoprecipitation assay. The proliferation and invasion of HT-29 cells were determined by CCK-8 and transwell assays. The nude mouse subcutaneous co-injection model was used to evaluate the growth of HT-29 cells in vivo. HSCs cultured on a stiff substrate (11 kPa) showed significantly higher OTUD5 expression compared to those in the soft substrate (2 kPa). OTUD5 knockdown prominently attenuated stiffness-induced HSC activation. The stiffness-induced increase in OTUD5 expression was significantly abolished by YAP knockdown in HSCs. YAP overexpression enhanced, while YAP knockdown and inhibition reduced OTUD5 expression. In turn, OTUD5 positively regulated YAP protein level and YAP target genes, such as CYR61 and CTGF, in HSCs. Co-immunoprecipitation and immunofluorescence assays confirmed the interaction between OTUD5 and YAP. Mechanistically, OTUD5 functioned as a deubiquitinase, removing the K48 ubiquitin chain from YAP and maintaining protein stability. Functionally, OTUD5 knockdown markedly attenuated HSCs-induced HT-29 cell proliferation and invasion in vitro and tumor growth in vivo. Our results highlight the critical role of OTUD5/YAP feedback loop in stiffness-induced HSC activation, offering a potential therapeutic target for colorectal liver metastasis.
Exercise-mediated regulation of mitochondrial dynamics in aging muscle: implications for mitochondrial diseases.
Zhang C, Zheng X, Xiang L … +1 more , Su Z
Mol Cell Biochem · 2026 Mar · PMID 41324861 · Publisher ↗
The deterioration of mitochondrial function is a hallmark of aging muscle and markedly accelerates the onset and progression of a range of mitochondrial diseases. Symptoms including limited mobility, persistent fatigue,...
The deterioration of mitochondrial function is a hallmark of aging muscle and markedly accelerates the onset and progression of a range of mitochondrial diseases. Symptoms including limited mobility, persistent fatigue, and muscle weakness are often attributed to impaired mitochondrial dynamics, involving key mechanisms such as mitophagy, fusion, and fission. Exercise has been shown to positively influence mitochondrial health by regulating mitochondrial biogenesis, dynamics, and turnover. This review examines the exercise-induced modulation of mitochondrial processes in aging muscle and delineates its prospects as an intervention for managing mitochondrial diseases. We highlight the molecular mechanisms by which exercise orchestrates mitochondrial dynamics, augments organelle function, and triggers mitophagy-all of which are crucial for the preservation of muscle cell homeostasis. Furthermore, we explore how pivotal molecular pathways such as AMPK, PGC-1α, and SIRT1 regulate mitochondrial adaptations to exercise. This review also underscores the therapeutic promise of exercise in attenuating mitochondrial disease progression via enhanced mitochondrial quality control and improved muscle function. By integrating findings from mitochondrial science, gerontology, and exercise physiology, this review positions exercise as a crucial regulator of mitochondrial dynamics and a viable non-pharmacological strategy for maintaining muscle integrity in the contexts of aging and mitochondrial disease.
Klotho in aging and diseases: molecular features, expressions, and functional implications.
Marwein M, Mukhim L, Sah P … +2 more , Nongbri D, Suchiang K
Mol Cell Biochem · 2026 Feb · PMID 41296273 · Publisher ↗
The protein Klotho, recognized for its anti-aging properties, has emerged as a significant focus in gerontological research due to its capacity to extend lifespan and confer protection against numerous age-associated pat...
The protein Klotho, recognized for its anti-aging properties, has emerged as a significant focus in gerontological research due to its capacity to extend lifespan and confer protection against numerous age-associated pathologies. Genetic ablation of the Klotho gene frequently precipitates accelerated aging phenotypes and systemic organ deterioration, functionally recapitulating the multi-organ decline observed in physiological aging. A substantial body of evidence substantiates the salutary effects of Klotho on various age-related tissue and organ insults. This review aims to delineate the multifaceted roles of Klotho in the aging process, emphasizing its intricate interactions with diverse metabolic pathways crucial for maintaining systemic homeostatic equilibrium. We underline how diminished Klotho levels, frequently observed in aged cohorts, contributing to the uncontrolled progression of age-associated diseases. Additionally, this review highlights the burgeoning therapeutic potential of Klotho protein as a viable intervention for ameliorating age-related conditions. Ultimately, this comprehensive review provides a nuanced understanding of Klotho biology, elucidating the molecular mechanisms by which it contributes to homeostatic regulation and confers protection against senescence-associated morbidities.
Five key challenges for the plasma membrane insertion of nicotinic acetylcholine receptors in cellular model systems.
Molitor LM, Steinritz D, Brockmöller S
Mol Cell Biochem · 2026 Feb · PMID 41296272 · Publisher ↗
Insertion of nicotinic acetylcholine receptors (nAChR) into the plasma membrane depends on their movement, organization and incorporation of lipid components. nAChRs are a highly investigated target in current therapeuti...
Insertion of nicotinic acetylcholine receptors (nAChR) into the plasma membrane depends on their movement, organization and incorporation of lipid components. nAChRs are a highly investigated target in current therapeutic research, including studies on channel opening and ion flow. Both areas require suitable cellular model systems, which are not readily available. Notably, muscle-type nAChRs can be generated in new transgene model systems. Despite minor successes, none of the existing model systems perfectly replicate the clustered, high-density receptors and their unique arrangement at the cell surface. This review examines the challenges which must be overcome to enable increased nAChR insertion into plasma membranes in artificial systems. We present models such as lipid rafts and the orchestration of protein-lipid interactions, and emphasize their relationship to nAChRs as a meshwork. Further studies reveal that membranes require particular lipid ingredients for the process of nAChR insertion. We examine the use of a picket-fence model with an extension of the dystrophin-associated glycoprotein complex (DGC) as a specialized picket for nAChR anchoring, clustering, and nanodomain formation. We specifically present the function of DGC as a special picket in nAChR platform formation for microaggregates and the signaling pathways involved in protein embedding in this DGC model. This provides insights into the issue of why nAChR insertion is minimal in artificial systems. The main aspects are evaluated by applying our transgene cellular model system. If these problems could be solved, it will be possible to develop improved cellular model systems with higher nAChR inserted densities in the future.
Cortical bone stem cell-derived extracellular vesicles: a preliminary characterization demanding mechanistic and functional validation.
Yang D, Yang J, Wang G
Mol Cell Biochem · 2026 Feb · PMID 41296271 · Publisher ↗
The recent study by Sasaki et al. (Mol Cell Biochem, 2025) presents a comparative analysis of extracellular vesicles (EVs) from cortical bone stem cells (CBSCs) and mesenchymal stem cells (MSCs), suggesting a unique prot...
The recent study by Sasaki et al. (Mol Cell Biochem, 2025) presents a comparative analysis of extracellular vesicles (EVs) from cortical bone stem cells (CBSCs) and mesenchymal stem cells (MSCs), suggesting a unique proteomic and functional profile for CBSC-EVs. While the study provides a valuable foundational characterization, its claims of superior regenerative potential require substantial validation. The proteomic data, though robust, remain correlative and lack mechanistic causation linking specific cargo (e.g., Sparc, Mmp14) to the observed pro-angiogenic effects in vitro. The absence of in vivo data in a pathophysiologically relevant bone regeneration model significantly limits the translational relevance of the findings. Furthermore, the exclusive focus on protein cargo overlooks the potential synergistic contribution of EV-encapsulated RNAs, presenting an incomplete picture of the CBSC-EV's molecular repertoire. The work by Sasaki et al. successfully identifies CBSC-EVs as a novel biological entity. However, its true impact hinges on future research that moves beyond description to establish causal mechanisms through targeted knockdown studies, validates functionality in complex in vivo environments, and adopts a multi-omics approach to fully decipher the EV cargo. Addressing these critical gaps is essential to determine whether CBSC-EVs represent a genuine therapeutic advance.
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