Search Results (1,430)

Background: Thymic epithelial tumors (TETs) are the most common primary neoplasms of the anterior mediastinum and present a dual classification challenge, namely anatomical staging according to the Masaoka–Koga system and histological risk stratification according to the World Health Organization (WHO) classification. Both tasks rely on expert pathological assessment and may be affected by interobserver variability. This study applied supervised machine learning (ML) to quantitative immunohistochemical (IHC) H-score profiles to predict Masaoka–Koga stage and WHO risk group in TETs. Methods: Logistic regression (LR) and XGBoost were applied to 19 biomarkers, including cellular localization, across two parallel analyses. Masaoka–Koga stage prediction was performed in 81 patients, including 59 early-stage and 22 advanced-stage cases, using the Synthetic Minority Oversampling Technique (SMOTE) across 100 train/test splits. WHO risk group prediction was performed in 89 patients, including 45 low-risk and 44 high-risk tumors, without oversampling. A cross-endpoint analysis applied the optimal Masaoka–Koga model to the WHO endpoint. Results: LR consistently outperformed XGBoost. The optimal Masaoka–Koga model combined Eph receptor A6 (EphA6) membranous, Yes-associated protein (YAP) nuclear, and histone deacetylase 4 (HDAC4) cytoplasmic H-scores, achieving an area under the curve (AUC) of 0.756. The optimal WHO model combined transcriptional coactivator with PDZ-binding motif (TAZ) cytoplasmic, EphA6 membranous, and YAP nuclear H-scores, achieving an AUC of 0.936. The Masaoka–Koga triad predicted WHO risk group with an AUC of 0.901. No tetrad improved trivariate performance. Conclusions: IHC H-score profiling combined with supervised ML identifies biologically interpretable candidate signatures for TET classification, although prospective external validation is required before clinical application. Full article

The mammalian sirtuins (SIRTs), consisting of seven members (SIRT 1–7), are NAD⁺-dependent histone deacetylases (HDACs). Similar to other classical NAD⁺-independent HDACs, SIRTs regulate a wide range of key biological processes by deacetylating both histone and non-histone proteins. By linking cellular metabolism to tissue homeostasis, SIRTs play important roles in physiological regulation and are often deregulated in many human diseases including diabetes, neurodegeneration and cancer, particularly sarcomas. Here, we reviewed the expression and roles of SIRTs, especially the most studied family member SIRT 1, across several types of human sarcomas, including both bone and soft tissues sarcomas. We also discussed the clinical relevance of SIRTs and the potential of their modulation as a therapeutic strategy in sarcomas. Full article

Testicular receptor 4 (TR4, NR2C2) is an orphan nuclear receptor involved in the regulation of metabolism, inflammation, cardiovascular disease, and cancer. Accumulating evidence indicates that TR4 exhibits functional plasticity, exerting protective or pathogenic effects depending on tissue and disease context, and sometimes displaying opposing roles within the same disease. However, the mechanisms underlying this functional duality remain poorly understood. Recent studies indicate that TR4 activity is determined not only by the receptor itself but also by dynamic coregulatory networks. Through interactions with coactivators, corepressors, epigenetic regulators, and environmental signaling pathways, TR4 integrates metabolic cues to generate context-dependent transcriptional programs. Coactivator networks centered on PGC-1α, steroid receptor coactivator (SRC) family members, and CBP/p300 support oxidative metabolism and anti-inflammatory responses, whereas RIP140-, NCoR/SMRT-, and HDAC-associated networks promote lipid accumulation, chronic inflammation, fibrosis, and tumor progression. Regulators such as JAZF1 further influence TR4 activity by reshaping coregulator recruitment and target-gene selection. In this review, we summarize the structural basis of TR4 regulation and discuss how coregulatory network remodeling governs its functions in metabolic, cardiovascular, inflammatory, and malignant diseases. We propose that TR4 functions as a context-dependent transcriptional platform whose activities are defined by its coregulatory landscape, providing a framework for precision therapies. Full article

Histone deacetylase 3 (HDAC3) is a key node linking immunometabolism, chromatin regulation, and inflammatory transcriptional programs. Rather than functioning simply as a nuclear deacetylase, HDAC3 output is jointly shaped by corepressor-complex assembly, metabolic and acyl-substrate availability, and compartment-specific substrate access. The identification of lysine lactylation and the discovery of delactylase activity in HDAC1–3 have expanded the mechanistic boundaries of HDAC3, repositioning it from a canonical deacetylase toward an emerging regulatory node involved in the dynamic control of multiple acyl modifications. This review examines the complex-dependent activation of HDAC3, its regulation of nuclear inflammatory transcriptional thresholds, the proposed redistribution of its catalytic output across acetylated and lactylated substrates under increased lactate load, and candidate extra-nuclear non-histone acylation networks involving inflammatory signaling proteins and metabolic enzymes. Current evidence supports bona fide delactylase activity of HDAC3 in biochemical systems; however, whether HDAC3 directly delactylates specific cytoplasmic substrates in physiologically relevant settings requires further validation at the compartmental, site-specific, and functional levels. Viewing HDAC3 as an immunometabolic rheostat helps explain its context-dependent functions in inflammatory homeostasis, acute activation, and metabolic stress, and provides a conceptual basis for developing selective, complex-state-sensitive, and function-stratified HDAC3-targeted strategies. Full article

Histone deacetylases (HDACs) are important epigenetic regulatory enzymes contributing to cancer proliferation, which could be critical targets in cancer therapy. The structural similarities of the existing HDAC inhibitors have resulted in an increase in the drug resistance. In this study, coumarin was employed as the core scaffold for structural derivatisation to develop a novel class of HDAC inhibitors based on computer-aided design (CADD). Their anti-tumor activity was evaluated against esophageal squamous cell lines. The results showed that most compounds exhibited potent anti-proliferative activity against KYSE70 and KYSE150. Among them, compound 4s and 4p exhibited the most potent activity with IC₅₀ values of 3.44 μM and 3.39 μM against KYSE70. To validate the target of the synthesized compounds, transcriptome sequencing was performed and the results revealed that a total of 487 genes were differentially expressed, including 190 up-regulated and 297 down-regulated genes. Among these, 79 genes were associated with the HDAC regulatory network, accounting for 16.2% of the differentially expressed genes. Molecular docking demonstrated that compound 4s could effectively enter the active site of HDAC, engaging with the cap group, zinc-binding group, and linker region. This multiple interaction network provides a structural basis for the potent inhibitory activity of compound 4s. In conclusion, a series of novel HDAC inhibitors with a coumarin scaffold were discovered, and their mode of action was revealed. This provides a valuable guide for the development of novel HDAC-targeting therapeutics. Full article

Background: Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Although immune checkpoint inhibitors (ICIs) have significantly improved clinical outcomes, most patients do not respond to treatment or fail to achieve durable responses. Histone deacetylase inhibitors (HDACi) have emerged as promising immunomodulatory agents, with the potential to sensitize tumors to ICIs. We investigated the immunomodulatory effects of entinostat, a class I HDACi, in combination with dual ICI (anti-PD-1 and anti-CTLA-4) as well as with T-cell receptor (TCR) engineered T cells in preclinical NSCLC models. Methods: We employed human NSCLC cell lines and the immunogenic KRASG12D/p53-mutant KPN1.1 murine NSCLC cell line. In vitro, we assessed entinostat-induced changes in MHC class I and PD-L1 expression. In addition, we evaluated the effects of entinostat on a KRASG12D-specific TCR. In vivo, therapeutic efficacy and immune modulation were assessed by transplanting KPN1.1 cells subcutaneously and orthotopically into immunocompetent mice, followed by treatment with dual ICI, with or without entinostat. Immune populations in the spleen and blood were subsequently analyzed. Results: In vitro, entinostat induced the upregulation of MHC-I and PD-L1 expression in both human and murine NSCLC cell lines. In addition, entinostat treatment significantly enhanced antigen-specific tumor recognition and killing by T cells engineered to express a KRASG12D-specific TCR. In vivo, the addition of entinostat to dual immune checkpoint inhibition showed an incremental trend toward improved tumor growth control. Notably, entinostat plus dual ICI enhanced systemic immune activation, increasing circulating and splenic T-cell populations and significantly expanding both antigen-specific and overall effector CD8⁺ T cells. Consistently, the ex vivo co-culture of splenocytes from KPN1.1-bearing mice with KPN1.1 tumor cells demonstrated enhanced CD8⁺ antigen-specific T-cell recognition. Conclusions: In human and murine NSCLC models, entinostat potentiates TCR- and ICI-mediated tumor recognition through tumor-intrinsic and systemic immune modulation. These effects were reflected by increased MHC-I expression, expansion of antigen-specific effector CD8⁺ T cells, and enhanced CD8⁺ T-cell tumor recognition. These findings support a further evaluation of entinostat as a strategy to improve immunotherapy efficacy in NSCLC. Full article

Skeletal muscle dysfunction (SMD) is a critical extrapulmonary comorbidity in chronic obstructive pulmonary disease (COPD), contributing to exercise intolerance, poor quality of life, and increased mortality. Building upon and extending the disuse model, this review synthesizes evidence establishing COPD-induced SMD as a distinct myopathy with intrinsic disease drivers. Its pathophysiology is driven by a self-reinforcing network: mitochondrial energetic crisis featuring bioenergetic failure and dysregulated dynamics, chronic oxidative stress and inflammation fueling catabolic drive via ubiquitin–proteasome system activation, and epigenetic dysregulation through alterations in key histone deacetylases (HDACs) and microRNA expression, which collectively orchestrate a pro-atrophic phenotype. We further explore how these molecular insights are translating into novel diagnostic tools, including circulating biomarkers like myomiRs and C-terminal agrin fragment, and imaging techniques such as shear wave elastography. Although exercise training remains the cornerstone of management, its limited efficacy underscores the need for adjunctive and targeted therapies. We discuss promising strategies from pharmacological and nutritional support to emerging agents targeting specific pathways, including the IL-36 receptor, lipoprotein-associated phospholipase A2, aryl hydrocarbon receptor, and mitsugumin 53. Effective management of COPD-related SMD will hinge on a precision medicine framework, leveraging biomarker-guided stratification to deploy personalized combinatorial interventions aimed at preserving muscle mass and function. Full article

Cancer stem cells (CSCs) drive therapeutic resistance and tumor relapse by exploiting redundant regulatory networks that integrate Wnt/β-catenin, Notch, and Hedgehog signaling with metabolic reprogramming, epigenetic plasticity, and tumor microenvironment crosstalk, a network architecture that renders single-pathway inhibition strategies insufficient. This review systematically examines evidence that natural compounds (curcumin, sulforaphane, resveratrol, EGCG, berberine, and quercetin) act as multitarget modulators of CSC plasticity, analyzing their molecular mechanisms of action in specific cancer models. Each compound engages distinct regulatory nodes: curcumin suppresses β-catenin nuclear translocation and STAT3 phosphorylation in lung cancer CSC models; sulforaphane represses ΔNp63α-driven stemness transcription in colorectal cancer and reduces CSC self-renewal in prostate and head and neck models; resveratrol dissociates the β-catenin–GLI-1 interaction in oral and lung CSC populations and induces Wnt/β-catenin-dependent autophagy in breast CSCs; EGCG inhibits DNMT and HDAC activity in glioblastoma and colorectal models; berberine activates AMPK-mediated suppression of mTORC1 in colorectal cancer; and quercetin suppresses PI3K/AKT/mTOR signaling while downregulating EMT transcription factors in breast and colorectal systems. We critically assess persistent methodological limitations, including bulk cell-line models, supraphysiological concentrations, and the absence of functional tumor-initiating validation, that currently prevent stronger translational conclusions. Natural compounds from Latin American biodiversity are identified as an underexplored source of CSC-active molecules. We conclude by defining the experimental standards required to reposition natural compounds as clinically relevant network-level modulators of CSC plasticity. Full article

Background: Although fentanyl significantly contributes to opioid-related morbidity and mortality, little is known about the epigenetic changes that may influence long-term neuronal adaptations. Objective: The effects of repeated fentanyl administration on class IIa histone deacetylase (HDAC) expression-activity were studied using the radiotracer [¹⁸F]TFAHA and positron emission tomography (PET) imaging in a model of fentanyl-induced behavioral sensitization. Methods: Female and male Wistar rats received 14 days of fentanyl (20 μg/kg) or saline injections and a 14-day drug-free period followed by a single fentanyl or saline challenge dose on day 28. Locomotor activity (LMA) was measured on days 0, 1, 14, and 28 with PET imaging being performed at baseline and again on day 28 following the fentanyl/saline challenge and LMA. The percent change in standard uptake value (body weight corrected) between pre- and post-administration was calculated as a measure of class IIa HDAC expression-activity. Results: Repeated fentanyl exposure resulted in significantly increased LMA in both sexes compared to controls. Females displayed an earlier onset (day 1) and a greater magnitude of behavioral sensitization on days 14 and 28 compared to males. Fentanyl significantly decreased class IIa HDAC expression-activity across time in the whole brain and in reward-related brain regions without sex differences. Conclusions: Prolonged fentanyl exposure induces robust sex-specific locomotor sensitization with varying magnitude over time, suggesting differential neuroadaptive processes. Fentanyl also appears to induce epigenetic changes in the brain independent of sex and region. The effect of fentanyl on class II HDACs may not directly impact the expression of behavioral sensitization. Full article

This study aimed to integrate apoptosis-associated and proliferation–apoptosis-coupled transcriptomic signatures with explainable machine learning to construct an exploratory molecular classification model for psoriasis. Transcriptomic datasets GSE30999 and GSE53552 were merged as the skin-tissue training cohort, and GSE55201, a whole-blood transcriptomic dataset, was used as an independent cross-tissue external validation cohort. Differential expression analysis identified 3707 DEGs, and intersection with GeneCards apoptosis-related genes yielded 894 overlapping genes. After PPI-based hub gene selection, eight machine learning algorithms were exploratorily compared within a preselected 25-gene feature space. DALEX-based permutation feature importance analysis identified a five-gene apoptosis-associated and proliferation–apoptosis-coupled signature comprising CCNB1, KIF11, HDAC1, TPX2, and MELK. The five-gene model achieved an AUC of 0.966 in the training cohort and 0.811 in the external whole-blood validation cohort, indicating moderate cross-tissue generalizability. Calibration and decision-curve analyses were performed only in the training cohort and should be interpreted as exploratory analyses rather than evidence of clinical utility. Overall, this study provides an interpretable transcriptomic classification framework for distinguishing psoriasis from healthy controls, while its ability to differentiate psoriasis from clinically similar dermatoses remains to be validated in independent disease-control cohorts. Full article

Epigallocatechin gallate (EGCG) is the major polyphenol in green tea and is frequently used in food supplements. In recent years, numerous studies have highlighted the bioactivity of polyphenols beyond their established role as radical scavengers. However, EGCG is highly unstable in slightly basic solutions such as cell culture medium. It therefore remains unclear whether the biological effects attributed to EGCG are caused by the parent compound itself or by its oxidation products, including the dimers examined here. In this study, the effects of EGCG focusing on apoptosis induction and histone deacetylases (HDAC) were compared with those of its major oxidation products, theasinensin A (TSA), theasinensin D (TSD), and oolongtheanin digallate (OTDG), in the human hepatocellular carcinoma cell line HepG2. The induction of cellular pathways involved in apoptosis was investigated using several in vitro biochemical approaches. Transcriptional analysis of apoptosis-associated genes revealed distinct expression profiles, and caspase activities were differentially affected by the test compounds. HDAC activity in nuclear protein extracts was significantly reduced after incubation with the stabilized oxidation products, whereas no comparable HDAC-inhibitory effect was observed after direct incubation of HepG2 cells. Nevertheless, HDAC gene expression, particularly of class I isoforms, was modulated by the test compounds in the low micromolar range. These effects diminished at concentrations associated with the onset of apoptosis. Furthermore, untargeted proteomics identified ribosomal proteins as additional cellular targets. Overall, these findings help to clarify the contribution of abundant EGCG oxidation products to the antiproliferative and HDAC modulating effects commonly attributed to the parent compound under cell culture conditions, underscoring the importance of investigating these oxidation products. Full article

Background: Severe malaria remains a major cause of morbidity and mortality, yet the conserved molecular signatures underlying complicated infections across Plasmodium vivax (P. vivax) and Plasmodium falciparum (P. falciparum) are not well characterized. Identifying shared transcriptional biomarkers and host–parasite interaction networks is crucial for improving diagnosis and discovering new therapeutic targets. Methods: Public transcriptomic datasets (GSE55644, GSE59844, GSE34404) were analyzed using GEO2R to identify differentially expressed genes (DEGs). Volcano plots, Venn diagrams, and KEGG mapping were used to identify conserved DEGs. Principal Component Analysis (PCA) and Support Vector Machine (SVM) models were used to assess predictive performance. Host–parasite cross-species correlation analysis integrated parasite DEGs with host hub-genes. Functional enrichment and network module analysis were performed using Cytoscape v3.10.2 and GO/KEGG annotation tools. Results: A total of 3363 DEGs were identified in P. vivax (GSE55644) and only one DEG in P. falciparum (GSE59844) using adjusted p-values, though 772 DEGs emerged with unadjusted p-values. Cross-dataset comparison revealed 18 common DEGs, with eight upregulated genes—TIM9, NUF2, SRP68, HDAC1, GRP94, DHHC8, PPM9, and RPL27—showing robust predictive performance (AUC = 1.000; CA = 1.000) for distinguishing complicated from uncomplicated malaria in both species. Host analysis identified 1719 DEGs and six hub-genes (TNF, IL6, TLR4, CR1, CD40LG, ICAM1) linked to apoptosis, Toll-like receptor signaling, complement cascades, and cell adhesion. SVM validation predicted parasitemia levels with 75.5–84.0% accuracy. Cross-species correlation revealed strong positive interactions between parasite HDAC1/GRP94 and host IL6/TNF and negative correlations involving NUF2, TIM9, ICAM1, and CR1. Functional enrichment analysis highlighted ER stress, immune activation, and erythrocyte adhesion pathways, which together form three major host–parasite modules. Conclusion: These findings highlight conserved biomarkers and potential therapeutic candidates for future validation, demonstrating that combined DEG profiling and machine-learning approaches can provide a powerful framework for improving diagnostics and intervention strategies for severe malaria. Full article

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, characterized by marked molecular heterogeneity, late-stage diagnosis, and limited therapeutic options. Emerging evidence highlights the interplay between cytoskeletal dynamics, epigenetic regulation, and oncogenic signaling pathways in hepatocarcinogenesis. Histone deacetylase 6 (HDAC6), a key regulator of cytoplasmic protein acetylation, modulates α-tubulin stability, while CTNNB1 (β-catenin) serves as a central effector of the Wnt signaling pathway. However, the existence and functional relevance of a coordinated HDAC6–TUBA1A–CTNNB1 regulatory axis in HCC remain insufficiently explored. We conducted a comprehensive integrative bioinformatic analysis using multiple publicly available datasets and platforms, including TCGA, GEO, GEPIA3, TNMplot, UALCAN, TIMER2.0, STRING, ENCORI, HPA, TargetScan, miRDB, CRISPRdb, GSCALite, and exoRBase. Gene expression, promoter methylation, survival associations, immune infiltration, regulatory RNA interactions, and therapeutic targetability were systematically evaluated. HDAC6 expression was significantly downregulated in HCC tissues, whereas TUBA1A and CTNNB1 were upregulated. Reduced HDAC6 expression was associated with poorer survival outcomes, while TUBA1A and CTNNB1 showed no significant prognostic value. Methylation analysis revealed gene-specific epigenetic alterations, including hypomethylation of CTNNB1 and differential methylation patterns in HDAC6 and TUBA1A. Immune infiltration analysis demonstrated that HDAC6 expression positively correlated with cytotoxic immune cell populations and negatively with immunosuppressive subsets. Regulatory network analyses identified lncRNA–miRNA–mRNA interactions, particularly involving SNHG1. Furthermore, in silico CRISPR targetability and extracellular vesicle (EV) transcript profiling suggested potential translational applicability of this axis. Our findings support a hypothesis of the existence of a dysregulated HDAC6–α-tubulin–β-catenin axis in HCC, linking cytoskeletal remodeling with oncogenic signaling and immune modulation. This axis may indicate a promising candidate for biomarker development and targeted therapeutic strategies, warranting further experimental validation. Full article

Non-Hodgkin lymphoma (NHL) encompasses a biologically diverse group of malignancies for which the integration of precision medicine has markedly reshaped therapeutic strategies. Recent advances in molecular profiling, target identification, and drug development have led to the introduction of highly selective agents capable of overcoming resistance mechanisms and improving outcomes in relapsed or refractory disease. This review highlights three targeted therapies—pirtobrutinib, brentuximab vedotin, and belinostat—and their evolving roles in modern NHL management. Pirtobrutinib, a next-generation, non-covalent Bruton tyrosine kinase (BTK) inhibitor, demonstrates preserved activity in patients previously treated with covalent BTK inhibitors (BTKi), addressing a critical unmet need in B-cell lymphomas. Brentuximab vedotin, an antibody–drug conjugate targeting CD30, has significantly improved therapeutic precision by delivering cytotoxic agents directly to lymphoma cells and has become a central component of treatment for CD30-expressing NHL subtypes. Belinostat, a broad-spectrum histone deacetylase (HDAC) inhibitor, offers a mechanistically distinct epigenetic approach, particularly in peripheral T-cell lymphomas (PTCL), where conventional chemotherapy has limited efficacy. Together, these agents exemplify three complementary paradigms of precision oncology in NHL: kinase signaling inhibition, antigen-directed cytotoxic delivery, and epigenetic modulation. This review synthesizes current evidence, clinical trial data, and future perspectives regarding the integration of pirtobrutinib, brentuximab vedotin, and belinostat into evolving treatment paradigms. Cumulatively, these therapies illustrate both the progress and the ongoing challenges of biomarker-driven treatment in NHL, including resistance mechanisms, toxicity management, optimal therapeutic sequencing, and variability in evidence maturity across targeted strategies. While pirtobrutinib and brentuximab vedotin are supported by increasingly robust clinical evidence in selected lymphoma subtypes, the role of belinostat remains constrained by modest response rates and limited randomized data, underscoring the continued need for biomarker refinement and more precisely individualized therapeutic approaches in NHL precision medicine. Full article

Piperine, the principal alkaloid of Piper nigrum, has gained attention as a multifunctional dietary compound with broad effects on epigenetic and transcriptional regulation in cancer and chronic diseases. Evidence shows that piperine modulates DNA methylation (↓ DNMT3B), histone acetylation (↓ HDAC activity), and microRNA networks (↑ miR-29c, ↓ miR-383), thereby reshaping key oncogenic and tumor-suppressive pathways. Beyond canonical epigenetic control, it can also stabilize G-quadruplex structures in promoters such as c-MYC, adding an architecture-based mechanism of transcriptional repression. Its dual redox behavior—antioxidant at low doses and pro-oxidant at higher doses—confers context-dependent selectivity, enabling oxidative stress–mediated apoptosis in tumor cells. Compared with other nutriepigenetic agents (curcumin, resveratrol, EGCG), piperine stands out for its multi-target profile and preliminary evidence of activity against cancer stem cell–like phenotypes. Nonetheless, limited solubility, rapid metabolism, and scarce in vivo validation constrain clinical translation. Future efforts should focus on advanced formulations, multi-omics approaches, and cancer stem cell models to better define its therapeutic potential and safety. Full article