Biomolecules最新文献

{"title":"Leucine-Rich Repeat Kinase 2 (LRRK2) in Glucose Metabolism and Metabolic-Neuroinflammatory Crosstalk.","authors":"Fumitaka Kawakami, Motoki Imai, Masanori Ogata, Toshiya Habata, Shun Tamaki, Rei Kawashima, Yoshifumi Kurosaki, Sayaka Miyai, Moragot Chatatikun, May Pyone Kyaw, Kenichi Ohba","doi":"10.3390/biom16040588","DOIUrl":"10.3390/biom16040588","url":null,"abstract":"<p><p>Leucine-rich repeat kinase 2 (LRRK2) is a multidomain serine/threonine kinase and a major genetic contributor to Parkinson's disease (PD). Although LRRK2 has been extensively studied in neurodegeneration, emerging evidence indicates that it also plays a critical role in systemic metabolism. LRRK2 regulates glucose homeostasis through modulation of insulin signaling, vesicle trafficking, mitochondrial function, and inflammatory responses. Studies using LRRK2 knockout and knock-in models, including the pathogenic G2019S mutation, have revealed abnormalities in insulin sensitivity, adipose tissue inflammation, hepatic glucose production, and skeletal muscle metabolism. Mechanistically, LRRK2 phosphorylates Rab GTPases, thereby controlling insulin receptor trafficking and GLUT4 translocation. In addition, LRRK2 influences mitochondrial dynamics and reactive oxygen species production, linking metabolic stress to inflammatory signaling. Importantly, LRRK2 also regulates innate immune pathways, including TLR4-NFκB signaling and inflammasome activation, thereby connecting peripheral metabolic dysfunction to neuroinflammation. Here, we propose an integrated metabolic-neuroinflammatory crosstalk model in which LRRK2 functions as a molecular coordinator linking peripheral metabolic dysfunction to central neurodegeneration. In this framework, systemic metabolic stress-characterized by insulin resistance, chronic inflammation, advanced glycation end product (AGE) accumulation, and blood-brain barrier disruption-drives microglial activation and neurodegenerative processes. Understanding this systemic axis may provide new therapeutic opportunities targeting both metabolic dysfunction and neurodegeneration in PD.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 4","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13113770/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147810872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chromatin Remodeling, DNA Double-Strand Break Repair, and Human Disease: How a Breakup Changes You.","authors":"Adriana Chiaramida, Christopher B Cummings, Thomas L Clarke","doi":"10.3390/biom16040589","DOIUrl":"10.3390/biom16040589","url":null,"abstract":"<p><p>Chromatin architecture is a central determinant of genomic stability. Effective DNA repair requires dynamic chromatin remodeling to grant repair factors timely access to lesions and to orchestrate repair pathway choice. Disruption of chromatin-regulatory mechanisms or DNA damage response pathways undermines repair fidelity and contributes to a wide spectrum of human disorders, including developmental syndromes, premature aging, and multiple cancers. Here, we review how chromatin state and remodeling complexes shape detection, signaling, and resolution of DNA double-strand breaks, and we examine how their misregulation drives disease and presents opportunities for therapeutic intervention. Specifically, we discuss how post-translational modifications and ATP-dependent chromatin remodeling complexes contribute to DNA damage repair with a particular focus on DNA double-strand breaks, one of the most deleterious DNA lesions. We summarize how chromatin remodeling and histone post-translational modifications regulate DNA repair pathway choice, and how these processes are essential for safeguarding genomic integrity and preventing human disease. Finally, we discuss emerging concepts and major unanswered questions in the context of chromatin function and DNA double-strand break repair, with a focus on exploring the emerging literature on the role of chromatin compartments and topological associated domains for orchestrating DNA repair within chromatin and safeguarding genomic stability.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 4","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13113357/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147810664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Iron Matters: Comparative Impact of Beta-Adrenergic Stimulation and Iron Chelation on Cardiac Iron Metabolism and Mitochondrial Function.","authors":"Josep Francesch-Manzano, Marta Tajes, Raúl Ramos-Polo, Cristina Enjuanes, Maria Del Mar Ras-Jiménez, Andreea Eunice Cosa, Katrin Marinova, Carla Enrich-Soria, Pedro Moliner, Laia Lorenzo-Esteller, Núria José-Bazán, Josep Comín-Colet","doi":"10.3390/biom16040582","DOIUrl":"10.3390/biom16040582","url":null,"abstract":"<p><p>Iron deficiency (ID) is frequent in patients with heart failure (HF) and is correlated with adverse outcomes, yet its involvement in HF pathophysiology is not fully understood. Hyperactivity of the sympathetic nervous system (SNS) is the central feature of HF. We aimed to compare the effects of isoproterenol (ISO), a β-adrenergic agonist (SNS stimulation), with those of the iron chelator deferoxamine (DEF), to evaluate how β-adrenergic stimulation influences cardiac iron. In this study, H9c2 cardiac cells were challenged with ISO, DEF or both and several parameters related to iron metabolism were analyzed. In all cases, the cells decreased their intracellular iron levels. ISO induced alterations in key cardiac iron metabolism molecules that were, in most cases, comparable to those elicited by DEF, emphasizing the direct impact of β-adrenergic stimuli on iron metabolism and mitochondrial dysfunction. Nevertheless, unlike DEF, ISO triggered a shift in mitochondrial energy metabolism. These findings suggest that β-adrenergic stimulation, as a major component of neurohormonal activation, may contribute to the development of ID in cardiac cells, highlighting the importance of iron homeostasis and the need to further investigate iron dysregulation in this context.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 4","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13113498/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147810863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Individual Effect of Bull Prevails over Sperm Characteristics in Predictive Models.","authors":"Adriano Felipe Perez Siqueira, Leticia Signori de Castro, Thais Rose Dos Santos Hamilton, Vivian Cardoso Castiglioni, Luana de Cássia Bicudo, Tamie Guibu Almeida, Rodolfo Daniel Mingoti, Camilla Mota Mendes, Roberta Leite, João Diego de Agostini Losano, Marcilio Nichi, Mayra Elena Ortiz D'Avila Assumpção","doi":"10.3390/biom16040581","DOIUrl":"10.3390/biom16040581","url":null,"abstract":"<p><p>Sperm quality influences bovine in vitro embryo production (IVEP). Linear regression is a statistical tool that models the relationship between a dependent variable and one or more independent variables. It can be used to predict outcomes, analyze trends, and understand the impact of variables. These models are useful for indicating which sperm variables most influence IVEP results, facilitating the selection of superior samples to enhance IVEP. Using early IVEP indicators, such as cleavage rate, can assist in scheduling recipient preparation. This work aimed to construct linear regression models to study the influence of a comprehensive set of sperm variables and cleavage rate on IVEP yields. A dataset comprising 51 semen batches from 23 Nellore bulls was compiled, including 26 sperm variables from computer-assisted sperm analysis (CASA) and flow cytometry per batch, with 184 IVEP procedures. The most robust predictive model had a coefficient of determination of 0.6358; furthermore, the BULL variable was the most influential predictor, yielding an independent coefficient of determination of 0.5218. Models that were exclusively founded on sperm analysis yielded meager coefficients of determination (<0.04). However, to predict the best batch from a bull, individual models achieve coefficients of determination ranging from 0.58 to 0.99. Contributions, impacts, and positive or negative correlations of various sperm variables with in vitro performance were influenced by the bull. We conclude that the BULL variable was the dominant predictor of in vitro performance, with cleavage rates serving as an early estimator of blastocyst rates. The predictive utility of analyzed sperm traits remains limited. Nonetheless, individualized models offer a valuable tool for selecting optimal batches for preferred bulls within IVEP laboratories, culminating in heightened blastocyst rates.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 4","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13113200/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147810785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure-Activity Relationships, Molecular Mechanisms, and Ecotoxicological Evaluation Underlying Nucleoside-Mediated Antifouling Activity.","authors":"Sandra Pereira, Isabel B Oliveira, Andreia Palmeira, Maria V Turkina, Vitor Vasconcelos, Alexandre Campos, Joana R Almeida","doi":"10.3390/biom16040584","DOIUrl":"10.3390/biom16040584","url":null,"abstract":"<p><p>Marine biofouling remains a major challenge for maritime industries, affecting submerged structures and vessels worldwide. The long-standing reliance on biocidal coatings, together with their documented environmental impacts, has led to increasingly restrictive regulations and an urgent demand for environmentally compatible antifouling (AF) solutions. This study evaluates the AF potential and toxicological profile of two nucleoside analogues, hypoxanthine arabinoside (<b>1'</b>) and 2'-deoxyinosine (<b>2'</b>), selected based on the previously reported non-lethal AF activity of the naturally occurring nucleosides adenosine and 2'-deoxyadenosine from cyanobacteria. Both analogues inhibited the growth of <i>Navicula</i> sp. by approximately 60% without inducing mortality and significantly reduced settlement of <i>Mytilus galloprovincialis</i> plantigrades, with EC₅₀ values of 5.50 µM (<b>1'</b>) and 8.54 µM (<b>2'</b>), and no lethality detected (LC₅₀ > 200 µM). At near-EC₅₀ concentrations, both compounds increased acetylcholinesterase and tyrosinase activities, supported by molecular docking results, suggesting involvement of neurotransmission- and byssal formation-related pathways. Proteomic analysis revealed compound-specific molecular responses. No lethal effects were observed in non-target organisms (LC₅₀ > 32 µM for <i>A. amphitrite</i> and LC₅₀ > 50 µM for <i>A. salina</i>), and environmental fate modelling predicted low bioaccumulation and rapid degradation. Overall, substitution of the amino group by a carbonyl group preserved AF efficacy without increasing toxicity, highlighting nucleosides as promising low-toxicity AF agents.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 4","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13114020/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147810772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Remodeling of the circRNA Landscape in Myocardial Infarction Integrates Nuclear Regulation, DNA Damage Response, and Cardiomyocyte Structural Pathways.","authors":"Rudaynah Alali, Naif Khalid Alqannas, Alawi H Habara, Mohammed Almansori, Ali Alsaeed, Chittibabu Vatte, Cyril Cyrus, Safi G Alqatari, Hassan Albisher, Mustafa H Al-Ajwad, Faisal S Alshahrani, Moyad M Almuslim, Morten T Venø, Brendan J Keating, Amein K Al-Ali","doi":"10.3390/biom16040578","DOIUrl":"10.3390/biom16040578","url":null,"abstract":"<p><p>Plasma circular RNAs (circRNAs) are stable RNA molecules found in blood, which makes them potential noninvasive biomarkers for acute myocardial infarction (MI). The aim of this study was to describe the plasma circRNA profile in patients with acute MI and to identify circRNA markers that may help detect heart injury and reflect the biological processes involved. We compared plasma samples from patients with acute MI and healthy controls using total RNA sequencing with unique molecular identifiers (UMIs). After sequencing, reads were processed through quality control, alignment, duplicate removal, and circRNA detection. Differential expression was analyzed after adjusting for age, sex, smoking, and technical factors. Several circRNAs were significantly different between MI cases and controls and were able to separate the two groups in principal component and receiver operating characteristic analyses. Among the most increased circRNAs were hsa-PASK_0004, hsa-STXBP3_0002, hsa-RCAN3_0002, and hsa-RANBP9_0044, while hsa-HIF1A_0002, hsa-SUZ12_0049, hsa-PNRC1_0001, and hsa-RAB2A_0002 were decreased. Several candidates showed AUC values above 0.7. Pathway analysis linked the host genes of these circRNAs to inflammation, platelet activation, coagulation, and cardiomyocyte stress responses. Overall, these findings suggest that circulating circRNAs may serve as useful blood-based markers of MI and provide insight into the molecular changes that accompany acute MI.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 4","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13113775/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147810693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extracellular Vesicles in the Gut-Vascular-Brain Axis: A Missing Mechanistic Link Between IBD and Stroke Risk.","authors":"Harshal Sawant, Erika L Butcher, Ji Chen Bihl, Subha Arthur","doi":"10.3390/biom16040577","DOIUrl":"10.3390/biom16040577","url":null,"abstract":"<p><p>Inflammatory bowel disease (IBD) is increasingly recognized as a systemic inflammatory disorder associated with elevated long-term risk of ischemic stroke, even among younger individuals without traditional vascular risk factors. Although chronic inflammation, endothelial dysfunction, and hypercoagulability partially explain this association, the biological mechanisms linking intestinal inflammation to cerebral vascular injury remain incompletely defined. Extracellular vesicles (EVs), membrane-bound particles released by epithelial, immune cells and platelets, have emerged as potent mediators of intercellular communication in inflammatory states. In IBD, circulating EVs are enriched with pro-inflammatory cytokines, microRNAs, adhesion molecules, tissue factors, which are capable of promoting endothelial activation, blood-brain barrier disruption, immune-thrombosis and neuroinflammation. This review summarizes epidemiologic, vascular, and EV biology literature to propose a mechanistic framework in which EV-mediated signaling integrates intestinal inflammation with cerebrovascular vulnerability along the gut-vascular-brain axis. While direct causal evidence remains limited, converging mechanistic data supports biological plausibility and defines priorities for future experimental and translational investigation.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 4","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13113477/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147810300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fluorescence-Guided Spatial Mapping of p21-Expressing Senescent Cells in Aged Liver at Single-Cell Resolution.","authors":"Jer-En Hsu, Binsheng Wang, Yongha Hwang, Weiqiu Cheng, Qingyang Zhao, Yichen Si, Ming Xu, Hyun-Min Kang, Jun Hee Lee","doi":"10.3390/biom16040579","DOIUrl":"10.3390/biom16040579","url":null,"abstract":"<p><p>Aging is a regulated process marked by the accumulation of senescent cells, which remain viable but no longer divide. Senescent cells contribute to age-associated phenotypes and diseases, including osteoarthritis, dementia, and cancer, but their scarcity and heterogeneity have limited study. Here, we developed a fluorescence-guided high-resolution spatial transcriptomic profiling approach to precisely locate and profile p21-reporter-positive cells in aged liver. This method enabled unbiased detection of a p21-associated, senescence-enriched cell population and revealed its diverse cellular identities, including hepatocytes, macrophages, neutrophils, and plasma cells. Our analysis further showed that activated macrophages and hepatic stellate cells were more likely to exhibit a p21 positive (p21⁺) state than their resting counterparts. Transcriptomic profiling of p21-expressing cells indicated heterogeneous senescence-associated secretory phenotype (SASP) programs, with distinct inflammatory and remodeling signatures across cell identities and their spatial positions. In parallel, we identified an aggregation of interferon-stimulated gene (ISG)-expressing cells with limited overlap with p21 positivity, suggesting a distinct aging-associated stress program. Taken together, our fluorescence-guided spatial transcriptomic framework enables high-resolution, single-cell mapping of senescence in situ, delineating both senescent cell type specificity and cell identity-independent senescence programs, thereby advancing a more comprehensive understanding of regulatory mechanisms underlying aging.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 4","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13113322/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147810367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthetic-Polymer-Based Cardiac Patches for MI-Induced Heart Failure Treatment: A Review.","authors":"Ahmed Eliwa, Mohamed K Abbas, Maryam Al-Ejji, Khadija Zadeh, Hamda Aboujassoum","doi":"10.3390/biom16040580","DOIUrl":"10.3390/biom16040580","url":null,"abstract":"<p><p>Myocardial infarction (MI) is one of the prevalent cardiovascular diseases, which is caused by obstruction of one or more coronary arteries, leading to cardiac tissue ischemia and death. One of the main consequences of MI is heart failure, which is defined as dysfunction of the heart muscle to pump blood into peripheral organs. Cardiac patches have drawn a lot of interest as a potentially effective way to restore damaged cardiac tissue and enhance its functionality. They are polymer-based scaffolds designed to be implanted on the heart surface, and they have shown a significant therapeutic effect in the treatment of MI by improving cardiac function and providing mechanical support for the infarction site by the delivery of various bioactive substances or cells. Several biomaterials with specific mechanical and chemical characteristics have been widely used as a scaffold in the process of fabricating cardiac patches. In this study, we focus on the latest developments in the manufacturing of synthetic-polymer-based cardiac patches used to treat heart failure induced by myocardial infarction. We describe the mechanical and chemical characteristics of several synthetic polymers and highlight the main benefits and drawbacks of each type. An overview of the major challenges and the future development directions in the field of cardiac patches is also highlighted.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 4","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13113715/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147810741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Theaflavin-3,3'-Digallate Targets Pin1 to Suppress Hepatocellular Carcinoma Malignant Proliferation Through Modulation of MAPK and PI3K/AKT Signaling Pathways In Vitro.","authors":"Shaoli Lv, Wenli Jiang, Jingyi Liu, Jiaxin Tao, Hui Zhong, Huaqing He, Xinling Liao, Jiayang Xie, Xiyuan Ouyang, Wang Wang","doi":"10.3390/biom16040583","DOIUrl":"10.3390/biom16040583","url":null,"abstract":"<p><p>Theaflavin-3,3'-digallate (TF3), a flavan-3-ol derivative found in black tea, exhibits anti-tumor activity, but its mechanism of action in hepatocellular carcinoma (HCC) remains to be elucidated. Here we systematically delineate how TF3 targets Pin1 to suppress HCC through an integrated approach combining computational simulations, enzyme assay and cell-based assays. TF3 spontaneously occupies the active site of Pin1 with a docking score of -8.9 kcal/mol, inhibiting its PPIase activity (IC₅₀ = 60.33 μmol/L) and yielding a binding constant (<i>K_a</i>) of 3.1 × 10⁵ mol/L. Drug affinity responsive target stability (DARTS) assays further corroborated that TF3 directly engages Pin1 within HCC cells. Functionally, TF3 potently suppressed the viability of HepG2, SK-Hep-1 and Huh-7 cells in both dose- and time-dependent manners (IC₅₀ = 61.22, 14.09 and 69.85 μmol/L at 24 h, respectively), and exhibited a modest selectivity window against the viability of L02 and THLE-2 cells (IC₅₀ = 133.43 and 90.29 μmol/L at 24 h, respectively). In addition, TF3 triggers mitochondrial-mediated apoptosis, evidenced by ROS accumulation, loss of mitochondrial membrane potential, an elevated Bax/Bcl-2 ratio, cytochrome c release and enhanced PARP cleavage, and induces G₂/M phase arrest. It also robustly inhibits HCC cell proliferation, invasion and migration, coinciding with downregulation of proteins governing cell cycle progression and invasive behavior. Transcriptome profiling coupled with enrichment analysis discovered that TF3 treatment differentially regulated 5009 genes, which were prominently enriched in pathways linked to apoptosis, cell cycle control, MAPK and PI3K/AKT signaling pathways. Western blotting analysis revealed that TF3 selectively suppresses phosphorylation of p38 and the PI3K/AKT cascade, activating JNK phosphorylation. In summary, our findings indicate that TF3 suppresses HCC proliferation by targeting Pin1, with attendant modulation of the MAPK and PI3K/AKT pathways, thereby presenting a potential candidate for targeted HCC therapy.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 4","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13113847/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147810851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}