Approximately 70% of clear cell renal cell carcinoma (ccRCC) patients harbor von Hippel‒Lindau (VHL) deficiency, which drives pseudohypoxia and metabolic reprogramming. Here, we report a histone H4 lysine 12 lactylation (H4K12la)-fueled phosphoglycerate kinase 1 (PGK1)-lactate positive feedback loop that sustains glycolytic flux in VHL-deficient ccRCC and is pharmacologically disruptable by glucocorticoids. H4K12la is markedly elevated in ccRCC tissues and is associated with advanced pathological stage and unfavorable patient outcome. Integrative transcriptomic and epigenomic profiling revealed that VHL deficiency amplifies H4K12la deposition at accessible promoters, coupled to transcriptional activation of glycolytic and tumor-promoting programs, exemplified by PGK1. Through high-content drug screening, we identify glucocorticoids as effective suppressors of H4K12la, which act via glucocorticoid receptor-mediated transcriptional repression of glycolytic genes and consequent attenuation of lactate production. Strikingly, VHL-deficient ccRCC exhibits greater on-target pathway sensitivity to dexamethasone at the H4K12la-glycolysis axis, and glucocorticoid dexamethasone potentiated the antitumor efficacy of the HIF-2α inhibitor belzutifan in both orthotopic cell line-derived and patient-derived xenograft models. Collectively, our findings establish H4K12la as a metabolic‒epigenetic amplifier in VHL-deficient ccRCC, reposition glucocorticoids as epigenetically active modulators that dampen lactate-driven chromatin activation and glycolytic output, and provide a mechanistically grounded combination strategy with HIF-2α blockade to target lactate-fueled transcriptional dependence in metabolically rigid tumors.

The persistence of latent HIV-1 reservoirs remains a major barrier to achieving a cure for HIV. While latency-reversing agents (LRAs) have been extensively studied, latency-promoting agents (LPAs) offer a complementary strategy to silence viral transcription and prevent immune activation. Here, we propose that modulation of IRF7-driven transcription may represent a novel approach to control HIV-1 latency, by characterizing the role of the Janus kinase 2 inhibitor (JAK2i) pacritinib as a novel latency-promoting agent (LPA).

Neurodegenerative diseases are complex disorders characterized by the progressive loss of neuronal structure and function, involving pathological mechanisms such as oxidative stress, chronic inflammation, protein misfolding, and impaired synaptic plasticity. Recent studies have revealed that epigenetic regulation plays a critical role in the onset and progression of these diseases, including mechanisms such as DNA methylation, histone modifications, and non-coding RNA regulation. Natural polyphenolic compounds, known for their safety and multi-target properties, have emerged as promising candidates for neuroprotection and therapeutic intervention.

In a randomised controlled trial (RCT), we compared the effects of treatment with furosemide + small volumes of hypertonic saline solution (HSS) with those of furosemide alone in patients with decompensated heart failure (HF), and their effects on inflammatory and remodelling markers and epigenetic signatures.

Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous subtype of breast cancer, with limited treatment options due to the absence of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2 (HER2) expression. This characteristic renders TNBC resistant to hormone-based and HER2-targeted therapies, leaving cytotoxic chemotherapy as the predominant strategy and highlighting the urgency for novel interventions. In this study, we investigated the mechanism of action of GL24, a potent 4-(phenylsulfonyl)morpholine-based small molecule with selective tumor suppression effects on metastatic TNBC cells, while being ineffective against TNBC cells derived from the primary tumor site, using gene co-expression analysis. By considering the distinct phenotypic responses induced by GL24, we tailored our co-expression analysis approach, selecting gene pairs that exhibited differential co-expression in effective cells while excluding gene pairs that also showed differential patterns in non-effective cells. Constructing a co-expression network from these differential pairs, followed by enrichment analysis and functional annotation, revealed specific gene interactions and molecular pathways associated with GL24-mediated TNBC inhibition. These insights supported the previously established findings that showed convergence on apoptosis based on differentially expressed genes, while also providing complementary information by highlighting pathways involved in metabolic alterations, proliferation, and migration or invasion. This expanded understanding advances the knowledge of the mechanisms of GL24 in combating TNBC.

Mitochondria are central to cellular homeostasis and play a critical role in aging and age-related disorders, making them promising therapeutical targets. Here, we identify terbinafine and miglustat as novel mitochondrial stress inducers that extend lifespan and improve healthspan in Caenorhabditis elegans. Through a two-step screening, we found that both compounds activate the mitochondrial stress response (MSR) and exhibit distinct mechanisms of action. Terbinafine and miglustat robustly activated the mitochondrial unfolded protein response (UPRmt) mediator ATFS-1, upregulated MSR pathways, and modulated mitochondrial function across species, similarly to doxycycline. Interestingly, both compounds also engaged the insulin/IGF-1 signaling (IIS) pathway in C. elegans, revealing an integrated stress response involving coordinated action of ATFS-1 and the FOXO transcription factor DAF-16, distinct from canonical IIS activation. Experiments in human HEK293T cells confirmed the translational potential, with both compounds inducing mitochondrial stress and modulating mitochondrial function in mammalian systems. This study highlights the potential of harnessing the MSR to promote longevity and mitigate age-related functional decline. The identification of terbinafine and miglustat as mitochondrial stressors paves the way for novel anti-aging therapies.

Triple-negative breast cancer (TNBC) is known for its more aggressive clinical behavior, poor prognosis, and distinctive patterns of metastasis. Neoadjuvant chemotherapy (NAC) can influence both tumor cells and the tumor microenvironment. Emerging evidence highlights the critical role of actin cytoskeletal dynamics in cancer progression.

Heart failure (HF) represents the terminal stage of various cardiovascular diseases, and its prevalence continues to rise while current therapeutic approaches remain insufficient to reverse disease progression. Epigenetic regulation, with a particular focus on histone methylation, has gained increasing attention for its involvement in the initiation and advancement of HF. Histone methylation is a reversible post-translational modification controlled by histone methyltransferases and demethylases, and it participates in essential biological processes such as gene expression regulation, cell cycle, apoptosis, and metabolic reprogramming. This review systematically summarizes the multifaceted roles of histone methylation in HF, including the specific functions in cardiac regeneration, hypertrophy, fibrosis, apoptosis, metabolic remodeling, and inflammation. The review also highlights the promising effects of inhibitors that target histone methylation enzymes in animal studies, including anti-hypertrophic, anti-fibrotic, and cardioprotective properties, suggesting significant potential for clinical translation.

Human immunodeficiency virus type 1 (HIV-1) is a retrovirus that integrates into the host cell's DNA as a provirus. Transcription from the provirus is regulated in large part by cellular proteins and epigenetic factors. These may be repressive or permissive to productive infection. The host factors that regulate this balance are therefore attractive targets for HIV-1 therapeutics. Indeed, proviral chromatin is the focus of two of the current HIV-1 cure strategies. "Shock and Kill" uses latency reversal agents to open the provirus's chromatin, promoting high levels of gene expression that induce the killing of infected cells. "Block and Lock" uses latency promoting agents to induce heterochromatin, blocking transcription and forcing HIV-1 into a state of deep latency. Here, the compounds investigated in both strategies are reviewed, including their chemical structures, mechanisms of action, and clinical results. Finally, the use of CRISPR-Cas therapeutics and the impact of chromatin architecture on its efficacy are discussed.

Background/Objectives: There is a clear need for more options to control the progression of breast cancer and prevent the occurrence of breast cancer in minority populations that have a higher rate of mortality due to triple-negative breast cancer (TNBC) subtypes. Prevalent nutraceuticals such as Ashwagandha (also known as the Indian Winter Cherry) have anti-inflammatory and apoptotic capabilities, as well as the ability to inhibit cancer growth. The purpose of this study is to analyze the novel combination of withaferin A (derived from the Indian Winter Cherry and known to have histone deacetylase inhibition capabilities) and sodium butyrate (a short-chain fatty acid produced from the gut microbiome and known to have DNA methyltransferase inhibition capabilities) treatment on breast cancer-derived cell lines. There is a scientific gap of possible causality of decreasing breast cancer progression when treated with sodium butyrate and withaferin A. Methods: Two in vitro cell viability assays were utilized consisting of [MTT (4,5 Dimethylthiazol-2-yl)] and the neutral red assay to analyze the impact of treatment of compounds alone and in combination on breast cancer cells for 72 h. The Highest Single Agent (HSA) combination analysis was utilized to derive combination indexes for our breast cancer cell types. Protein and gene expression was investigated for Class 1 histone deacetylases, de novo DNA methyltransferase, the p65 subunit of NF-κB, and NFκB1. Lastly, DNA methyltransferase enzymatic activity was analyzed via the Epigentek DNMT Activity/Inhibition ELISA Easy Kit. Results: Through the cell viability assay [MTT (4,5 Dimethylthiazol-2-yl)], MCF-7, MDA-MB-231, and MDA-MB-157 cells were found to have a decrease in cell viability due to combinatorial treatment with withaferin A and sodium butyrate. Western blot results depicted a decrease in protein expression levels for DNA methyltransferases due to the administration of 2.5 mM sodium butyrate and 0.2 µM withaferin A alone and in combination for breast cancer cell lines MCF-7, MDA-MB-231, and MDA-MB-157. Additionally, the combination of these two components have successfully inhibited the progression of the NFκB1 gene within analysis through the quantitative polymerase chain reaction (qPCR). Conclusions: The novel combination of withaferin A and sodium butyrate have markedly reduced the progression of breast cancer-derived cell lines for cell viability, epigenetic DNMT gene expression, as well as inhibiting NFκB1 signaling on the gene expression level.

Environmental exposure to heavy metals, particularly cadmium (Cd), has been increasingly associated with obesity, metabolic dysfunction, chronic inflammation, and related disorders such as type 2 diabetes and cardiovascular diseases. Adipose tissue (AT), a paracrine and endocrine organ central to systemic energy and inflammatory homeostasis, is a major site of heavy metal accumulation and a key target of Cd toxicity. However, the mechanisms by which Cd disrupts adipocyte function, especially through epigenetic pathways, remain poorly understood. In this study, we investigated the effects of Cd on epigenetic regulators, antioxidant enzyme activity, inflammatory mediators, and adipogenic programming in human adipose-derived stromal/stem cells (hASCs) and differentiated adipocytes. Cd exposure altered histone modifiers associated with lysine 27 of histone 3 (H3K27), disrupted redox balance in a concentration-dependent manner, impaired adipogenic differentiation and lipid accumulation, and modulated inflammatory and adipokine responses according to differentiation stage and Cd concentration. Our findings suggest that Cd compromises adipose cell homeostasis through mechanisms involving epigenetic dysregulation, oxidative stress imbalance, and altered adipogenic and inflammatory signalling. These observations point to possible long-term metabolic consequences of environmental Cd exposure due to its accumulation in adipose tissue.

Triple-negative breast cancer (TNBC) cells with intact homologous recombination (HR) repair mechanism can survive treatment with Olaparib, which further limits the clinical application of PARP1/2 inhibitors. Previous studies have demonstrated that inhibition of indoleamine 2,3-dioxygenase (IDO) can enhance the sensitivity of human tumor cells to PARP1/2 inhibitors. However, the mechanisms underlying their synergistic effects in the treatment of TNBC remain unclear. Herein, we demonstrate that the combination of Olaparib and Epacadostat significantly reduces the proliferation of BRCA-proficient MDA-MB-231 and MDA-MB-468 cells compared to either monotherapy. Mechanistically, Epacadostat reduces intracellular kynurenine and NAD+ levels, thereby sensitizing TNBCs to PARP1/2 inhibition and significantly amplifying Olaparib-induced DNA damage. Furthermore, Epacadostat and Olaparib synergistically increase cellular reactive oxygen species (ROS), leading to DNA oxidative damage and apoptosis. In vivo, Epacadostat and Olaparib significantly suppressed MDA-MB-468 tumor growth compared to the monotherapy groups, while promoting an increase in phosphorylated H2AX. Notably, the dual inhibition of IDO1 and PARP1/2 specifically reduced the expression of HR core genes and proteins, such as BRCA1 and RAD51, which may contribute to impaired DNA-damage repair and increased sensitivity to Olaparib. In summary, targeting both IDO1 and PARP1/2 represents a promising combination therapy for BRCA-proficient TNBC.

S-phase kinase-associated protein 2 (SKP2) is an oncogene and cell cycle regulator that mediates the ubiquitination of cell cycle regulators. Curcumol, a sesquiterpene natural product, has been reported to regulate SKP2-mediated ubiquitination degradation to overcome drug resistance in cancer cells. However, whether the cell cycle arrest effect of curcumol is related to SKP2's function in cancer cells and its mechanisms are still unclear.

Biochar, a carbon-rich material traditionally used to improve soil health and as a feed additive, has recently attracted attention for its potential biological activity. This study examined the effects of an aqueous biochar extract (BC-AE) on human intestinal epithelial cells (Caco-2), focusing on its influence on cell viability and apoptosis. The metabolic activity of Caco-2 cells exposed to BC-AE was first evaluated using an MTS assay. A concentration of 3 mg/mL, which promoted Caco-2 metabolic activity, was selected for further testing at 24 and 72 h. The effect of BC-AE on cell viability was assessed by epifluorescence microscopy (morphology) and flow cytometry (apoptosis profiling). The transcriptional response of cell viability-related genes (BAX, BAD, BCL-2, BCL-xL, MCL-1, P21, and P53) and microRNAs (miR-15b, miR-19, miR-21, miR-33a, miR-155, and miR-486) was analyzed by RT-qPCR. In parallel, selected proteins (BAD, BAX, BCL-2, and MCL-1) were examined by Western blotting. We showed that BC-AE decreased cell viability after 24 h via late apoptosis, while 72 h exposure increased necrosis without further viability loss. Both BAX and MCL-1 protein levels increased in Caco-2 cells after 72 h of BC-AE treatment, and miR-15b and miR-21 were upregulated, suggesting the involvement of a regulatory mechanism controlling cell survival. The obtained findings highlight the importance of considering both concentration and exposure duration when assessing biochar bioactivity and represent an additional contribution to the ongoing effort to better understand the biological role.

Breast cancer represents a persistent global health burden, marked by extensive molecular heterogeneity and frequent therapeutic resistance in aggressive subtypes, particularly triple-negative breast cancer (TNBC). These clinical challenges underscore the urgency for alternative therapeutic strategies. Bioactive alkaloids isolated from Nelumbo nucifera, especially the bisbenzylisoquinoline compounds liensinine (LIE), isoliensinine (ISO), and neferine (NEF), have emerged as promising candidates due to their ability to disrupt oncogenic signaling pathways and inhibit malignant cellular transformation. The present study conducted a systematic investigation of LIE, ISO, and NEF across multiple breast cancer cell lines, including highly aggressive TNBC models. Results revealed potent growth-inhibitory effects mediated through apoptosis induction and cell cycle arrest at both the G1 and G2/M phases. Furthermore, transcriptomic profiling and molecular analysis identified LIE as a principal effector, driving extensive transcriptional reprogramming and targeting the MAPK and mTOR pathways as core regulators of its anti-cancer efficacy. Collectively, these findings define a mechanistic framework for the anti-cancer potential of N. nucifera-derived alkaloids and provide a compelling foundation for their development as therapeutic candidates for advanced breast cancer.

Fumonisin B1 (FB1) is a toxic secondary metabolite produced by Fusarium species that commonly contaminates cereal crops, posing serious threats to crop productivity and food safety. In plants, FB1 inhibits ceramide synthase, disrupts sphingolipid metabolism, and induces growth inhibition and programmed cell death. Despite the agricultural importance of fumonisin contamination, genetic strategies to enhance FB1 tolerance or detoxification capacity in crops remain limited, largely due to an incomplete understanding of the underlying genetic determinants.

Background/Objectives: Programmed death ligand 1 (PD-L1) is often overexpressed in triple-negative breast cancer (TNBC), where it helps the tumor evade the immune system and promotes tumor growth. Interleukin-24 (IL-24) is recognized for its anti-tumor activity, although its role in immune regulation remains unclear. In this study, we examined the role of IL-24 in regulating PD-L1 and its anti-cancer activity in TNBC cells.

Background: Obesity is associated with hypothalamic dysfunction characterized by neuroinflammation and altered transcriptional programs. While resveratrol (RSV) has shown beneficial metabolic effects in peripheral tissues, its central effects on hypothalamic gene expression in obesity remain poorly understood. This study provides the first predictive transcriptomic analysis of the hypothalamic response to RSV in a mouse model of diet-induced obesity. C57BL/6 male mice were fed a high-fat diet (HFD) to induce obesity and then subsequently treated with RSV. Methods: Hypothalamic RNA was extracted and analyzed using RNA sequencing. Differentially expressed genes (DEGs) were identified and functionally analyzed through KEGG pathway analysis. Results: Although RSV did not significantly alter body weight, it reversed the expression of several HFD-induced DEGs. Key genes modulated by RSV included Aqp7, Ccl27a, Lta, Rilp, M6pr-ps, C1ra, Snail1, Gbgt1, and Ppargc1b, which are involved in inflammation, lipid metabolism, mitochondrial function, and immune signaling. Pathway enrichment analysis revealed significant modulation of TNF and NF-κB signaling, cytokine-cytokine receptor interactions, glycosphingolipid biosynthesis, and phagosome-related activity. Remarkably, 45% of RSV-responsive transcripts were non-coding RNAs, suggesting epigenetic regulation. Conclusions: RSV reprograms the hypothalamic transcriptome in obesity, targeting both coding and non-coding RNAs associated with inflammation and metabolic regulation, independently of weight loss. These findings identify RSV as a potential central modulator of metabolic dysfunction and highlight the hypothalamus as a promising therapeutic target in obesity-related disease.

Di(2-ethylhexyl) phthalate (DEHP) is a high-production-volume plasticizer and ubiquitous environ-mental contaminant with established endocrine-disrupting potential. While zebrafish transcriptomic studies have typically used high concentrations and long exposure windows, less is known about genome-wide responses during late embryogenesis/early larval maturation under environmentally relevant exposures. Here we profiled whole-organism transcriptomic responses to a short DEHP exposure during a developmentally sensitive transition (96-120) hours post-fertilization, hpf) and interpreted responses using differential expression, enrichment analyses, and endocrine-focused protein-protein interaction (PPI) network modeling.

Bladder cancer (BCa) is the second most common cancer of the genitourinary tract globally. It has limited treatment options, high recurrence rate, and acquires resistance to platinum-based therapy. Therefore, identifying novel therapeutic targets is urgently needed. Analysis of the TCGA data revealed that the enzyme galactokinase-1 (GALK1) is overexpressed (p < 0.0001) in bladder tumors compared to normal tissue. Our data also confirmed GALK1 protein upregulation in multiple human BCa cell lines and rodent bladder tumors. However, the precise role of GALK1 in BCa progression and effects of its specific inhibitor remain unexamined. In this study, we demonstrate that GALK1 gene silencing using shRNA resulted in a significant reduction in BCa cell proliferation, migration, and invasion. Pharmacological inhibition of GALK1 using small molecule Cpd36 resulted in anticancer efficacy against BCa. Cpd36 inhibited proliferation, migration, and invasion of BCa cells. Further, Cpd36 induced G1 phase cell cycle arrest, apoptosis, mitochondrial membrane depolarization, and ROS production in the BCa cells. Mechanistically, Cpd36-induced reduction in cell proliferation was associated with a decrease in expression of GALK1, PCNA proteins. Inhibition of metastatic potential was accompanied by decreased migration, invasion, and MMP-9 expression. Cell cycle arrest was associated with decrease in Cyclin D1 and increased expression of p21 and p27. Induction of apoptosis was linked with increased expression of cleaved caspase-3 and cleaved PARP, while downregulating p-AKT. Additionally, Cpd36 in combination with cisplatin or gemcitabine showed a strong synergistic effect on BCa cells. Taken together, our findings suggest that GALK1 plays a significant role in BCa cell survival and validates its inhibitors as promising therapeutic options for managing this disease.