Obesity represents a global health concern, with the hypothalamus playing a central role in regulating energy balance. Chlorpyrifos (CPF), a widely used organophosphate pesticide, is now recognized as an endocrine-disrupting chemical (EDC). Although the peripheral metabolic effects of CPF are relatively well characterized, its potential impact on central energy balance remains to be investigated. Here, we examined, both in vitro in murine hypothalamic cells and in vivo in murine hypothalami, whether CPF modulates the orexigenic mediators Neuropeptide Y (Npy) and Agouti-related peptide (Agrp). We further explored the molecular mechanisms underlying this regulation.

Acquired resistance to paclitaxel represents a critical barrier to the effective chemotherapy of non-small cell lung cancer (NSCLC). The present study aimed to elucidate the molecular and pharmacological mechanisms promoting paclitaxel resistance in NSCLC and to explore potential strategies for overcoming this resistance.

While cisplatin-based chemotherapy is pivotal for advanced bladder cancer, acquired resistance remains a major obstacle. This study investigates key molecular drivers of this resistance and potential reversal strategies.

Immune checkpoint blockade (ICB) therapies for triple negative breast cancer (TNBC) have yielded limited clinical benefits, which may be attributed to the immunosuppressive tumor immune microenvironment (TIME). Glucocorticoid receptor (GR) has long been thought to suppress immunity by acting on immune cells in the TIME, but no studies have investigated its function in TNBC immunotherapy.

Ultraviolet (UV) radiation is a key environmental factor contributing to photoaging, inflammation, and carcinogenesis. While sunscreen is known to prevent sunburn and lower cancer risk, its effectiveness in limiting UV-induced molecular alterations in human skin is not fully defined. In this study, 32 female volunteers belonging to four Fitzpatrick phototypes underwent repeated moderate UV exposures, with skin samples collected from three distinct treatment sites on each participant, including untreated, UV-exposed without protection, and UV-exposed with prior application of sunscreen. Comprehensive profiling revealed that UV exposure markedly altered gene expression and DNA methylation, impacting pathways involved in DNA repair, immune response, and cell cycle regulation. Mapping these molecular signatures to the Hallmarks of Health revealed broad disturbance of the skin's core functional attributes. The application of sunscreen effectively prevented most UV-driven disruptions, including the acceleration of epigenetic age, and maintained the stability of hallmark-associated pathways, with minor residual molecular changes remaining. This study demonstrates the importance of regular photoprotection in preventing visible skin damage and maintaining molecular skin health. By deepening our understanding of the mechanisms underlying photoprotection, these findings also indicate a new scope for further advancements in the efficacy of future sunscreen formulations.

Targeting the protein quality control system in Mycobacterium tuberculosis represents a promising and underexplored opportunity for antibiotic development. The ClpC1:ClpP1P2 protease is an essential component of the system that mediates both regulatory and stress-related protein degradation. Several non-ribosomal peptide natural products, including ecumicin, ilamycins (rufomycins) and cyclomarins, have been discovered that bind to the ClpC1 chaperone of the complex and exhibit potent antimycobacterial activity, leading to significant interest in the ClpC1:ClpP1P2 system as a bona fide target for the new tuberculosis drugs. In this study, we combine quantitative proteomics, bioinformatics, transcriptomics, CRISPRi knockdown, and targeted biochemical and biophysical assays to dissect the mechanisms of ecumicin, ilamycin and cyclomarin in clinically relevant Mycobacterium tuberculosis. Strikingly, despite exhibiting similar binding modes to ClpC1, each compound induces distinct effects on protein degradation. Notably, ilamycin and ecumicin do not trigger the ClpC2 rescue mechanism that mitigates cyclomarin-induced mycobacterial toxicity. In addition, we identify a novel interaction between ecumicin and stress-response chaperone Hsp20. The differential disruption of ClpC1 substrates, stress-response chaperones, and distinct reshaping of the Mycobacterium tuberculosis proteome by the three natural products, unveils new opportunities for the development of protein quality control-targeted antimycobacterials.

Despite the significant potential of photodynamic therapy (PDT) in cancer treatment, further refinement is needed to address challenges such as poor tumor-specific accumulation of photosensitizers and the development of therapeutic resistance, which may be regulated by epigenetics. Here, a novel tumor microenvironment-responsive delivery platform was developed to co-deliver epigenetic protein degraders and photosensitizers, aiming to block the relevant regulatory mechanisms and enhance the effectiveness of combination therapy. Benefiting from the targeting ability, pH-triggered charge reversal, and intracellular glutathione (GSH)-responsive release, the delivery platform exhibited enhanced tumor accumulation and therapeutic effects. The mechanism of action revealed that the precise accumulation and release of drugs via the tumor-orchestrated delivery system not only regulated cell growth and immune activation, but also inhibited the expression of tumor immune escape molecules (PDL1 and CD47) and M2 macrophage polarization, significantly increasing the anti-breast cancer and anti-melanoma effects of PDT in the presence of an epigenetic modifier. More importantly, we found for the first time that photodynamic therapy can generate therapeutic resistance through the upregulation of CCL5, and confirmed that this resistance can be reduced by the epigenetic degradation of bromodomain-containing protein 4 (BRD4). These findings underscore the potential of integrating PDT with epigenetic protein degraders through a programmed delivery platform, offering a promising strategy for improving cancer treatment outcomes.

Low-temperature plasma (LTP) is an essential technology in engineering that originated in materials science. Its applications have recently been expanded to biology, where it is referred to as plasma biology. LTP and LTP-activated solutions are now used for wound healing and sterilization. One emerging field is cancer treatment.

Sex differentiation in zebrafish is governed by a complex interplay of genetic and endocrine signals. Triploid zebrafish, which are largely sterile, consistently develop as males, but the underlying mechanisms remain elusive. Here, we combined histological and transcriptomic analyses to examine how triploidy and exposure to 17α-ethinylestradiol (EE2) modulate sex differentiation in zebrafish. Triploidy disrupted hormonal and paracrine signaling, with downregulation of fshr and amh, upregulation of igf3, potential activation of β-catenin pathway, and suppression of ptger2a and dio1, resulting in complete masculinization. In diploids, EE2 exposure resulted in a wide range of gonadal phenotypes, from testes and ovotestes to fully developed ovaries, reflecting the complexity and variable sensitivity of zebrafish sex differentiation to hormonal stimuli. Potential mechanistic insights underlying these outcomes are provided. By contrast, long exposure of triploid zebrafish to EE2 promoted the expansion of early germ cells, but failed to induce ovarian differentiation, suggesting a fixed male trajectory induced by triploidy. Triploids also showed a distinct endocrine state, lacking the EE2-induced suppression of cyp11c1 observed in diploids, suggesting altered corticosteroid homeostasis that may reinforce masculinization. Both triploidy and EE2 administration altered meiosis and spermiogenesis, consistent with the downregulation of klhl10 and constrained retinoic acid signaling through dhrs3a and/or cyp26b1. At the molecular level, both triploidy and EE2 converged on suppression of early steroidogenic genes, including star and cyp11a1, indicating limited androgen and estrogen biosynthesis. Together, these findings reveal how triploidy reshapes endocrine regulation and responsiveness and reveal shared and unique molecular pathways by which EE2 influences zebrafish gonadal fate.

Turmeric-derived exosome-like nanoparticles (TELNs) are nanoscale vesicles of plant origin with therapeutic potential. However, the specific efficacy and mechanisms of TELNs in inhibiting non-small cell lung cancer (NSCLC) remain unclear. This study investigated the effects of TELNs on NSCLC by epigenetically regulatiing histone acetyltransferase human males absent on the first (hMOF) and histone H4K16 acetylation (H4K16ac).

Endocrine-disrupting chemicals (EDCs), including bisphenol A (BPA), phthalates, organochlorine pesticides, and heavy metal ions, pose serious threats to reproductive health by interfering with hormonal balance and molecular signaling pathways. Recent research had expanded our understanding of these compounds has beyond their traditional role in hormone receptor interference. EDCs can trigger lasting epigenetic changes, including abnormal DNA methylation, histone modifications, RNA methylation, and altered regulation of non-coding RNA, which can impair reproductive functions such as gametogenesis, folliculogenesis, steroidogenesis, and embryo implantation. Importantly, EDC-mediated epigenetic alterations have been linked to various reproductive disorders, including polycystic ovary syndrome (PCOS), endometriosis, reduced ovarian reserve, and impaired spermatogenesis. For example, BPA exposure alters DNA methylation in estrogen signaling and aromatase gene expression, whereas phthalates disrupt histone acetylation and methylation in hormone synthesis pathways. Similarly, pesticides and heavy metal ions may influence microRNA expression and histone structure, further disrupting endocrine-regulated gene networks. These alterations may occur during sensitive developmental windows and can lead to long-term or transgenerational effects on reproductive health. Understanding how EDCs exert their toxicity through epigenetic mechanisms is essential for early detection of exposure, identification of molecular biomarkers, and development of targeted therapies to reduce reproductive risks. Here, we discuss the emerging molecular evidence that provides a comprehensive overview of how EDCs impair reproductive health through epigenetic pathways, thereby offering a framework for future research and translational applications.

Recent studies have extensively addressed the potential role of the autonomic nervous system, which extensively innervates the pancreas, in the development of pancreatic ductal adenocarcinoma (PDAC). Targeting hypoxia-inducible factor-1 (HIF-1) for cancer management has attracted significant research interest, in view of the finding that HIF-1 regulates the expression of various genes involved in tumor angiogenesis, metastasis, proliferation, chemoresistance, and radioresistance. In this study, we investigated the molecular mechanisms by which the neurotransmitter acetylcholine enhances the expression of HIF-1α in pancreatic cancer cells in hypoxia. Under hypoxic conditions, acetylcholine induced a concentration-dependent increase in nAChR-α7-mediated HIF-1α expression in pancreatic cancer cells in vitro, leading to enhanced expression of HIF-1α target genes. It also increased HIF-1α protein stability in pancreatic cancer cells under hypoxic conditions. The acetylcholine-induced elevation of HIF-1α expression was blocked by siRNA-mediated knockdown of PDPK1/YAP signaling, indicating a role for this pathway in mediating these effects. A bioinformatics analysis of publicly available clinical datasets revealed that overall survival was significantly poorer in patients with CHRNA7 copy number amplification, whereas those with high CHRNA7 mRNA expression showed a non-significant trend toward reduced survival, suggesting that copy number alterations have stronger clinical relevance than mRNA levels. Functionally, α-bungarotoxin, a nAChR-α7-specific inhibitor, markedly blunted the acetylcholine-induced increase in the viability of pancreatic cancer organoids under hypoxic conditions. In a mouse xenograft model, acetylcholine administration accelerated tumor growth in animals bearing control pancreatic cancer cells but not in those implanted with nAChR-α7-knockdown cells. Collectively, our findings reveal a novel mechanism of acetylcholine-induced enhancement of HIF-1α expression involving PDPK1/YAP signaling and highlight the utility of HIF-1α as a therapeutic target in acetylcholine-potentiated pancreatic cancer.

Liver fibrosis is a pathological outcome of chronic liver injury and is primarily driven by the continuous activation of hepatic stellate cells (HSCs). During activation, HSCs depend on aerobic glycolysis to maintain their fibrogenic characteristics, suggesting that metabolic reprogramming could serve as an effective therapeutic approach. In this study, we demonstrate that Curcumol, a natural compound derived from plants in the Zingiberaceae family, selectively removes activated HSCs by interfering with the lactate-KAT8-HK2 regulatory pathway. In HSCs, lactate produced through glycolysis activates the acetyltransferase KAT8, which catalyzes K346 lactylation of hexokinase 2 (HK2). This modification creates a positive feedback mechanism that stabilizes HK2. Curcumol acts directly on KAT8, inhibiting HK2 lactylation and promoting HUWE1-mediated ubiquitination and degradation of HK2. The resulting loss of HK2 removes its inhibitory influence on RIPK1 ubiquitination, leading to activation of the RIPK1/RIPK3/MLKL signaling pathway and triggering necroptosis. In vivo experiments show that Curcumol substantially reduces liver fibrosis, lowers the expression of glycolytic enzymes, and improves liver function in mice with carbon tetrachloride (CCl₄)-induced fibrosis. However, these protective effects are lost when KAT8 is overexpressed. This study highlights HK2 lactylation as a key metabolic control point for HSC survival and identifies Curcumol as a potential anti-fibrotic compound that targets the KAT8-HK2 pathway, linking metabolic inhibition with necroptotic cell death.

Colorectal cancer (CRC) is counted among the most widespread malignancies worldwide, characterised by elevated incidence and mortality rates. Conventional chemotherapy is frequently associated with severe toxic side effects and the development of drug resistance, which necessitates an urgent search for alternative therapeutic modalities. Traditional Chinese medicine (TCM), distinguished by its multi-component and multi-target synergistic actions, represents a promising prospect for the development of innovative anti-tumour therapies. Nitidine chloride (NC), a major bioactive component isolated from Zanthoxylum nitidum, has demonstrated notable anti-tumour activity in various cancer types. However, the specific molecular mechanisms underlying its anti-CRC effects remain unclear. Centromere-associated protein E (CENPE) exerts a pivotal function in the regulation of the cell cycle, and its aberrant expression has been documented in multiple malignancies. It may therefore serve as a potential therapeutic target. This study sought to clarify the interplay between NC and CENPE, with the aim of offering a scientific foundation for the advancement of precision therapeutic approaches for CRC utilising TCM-derived bioactive compounds. To comprehensively characterise the expression pattern of CENPE in CRC, we integrated a range of state-of-the-art technologies encompassing single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, large-scale mRNA cohort analyses and immunohistochemistry (IHC). The regulatory impact of NC on CENPE expression was verified through real-time quantitative polymerase chain reaction (RT-qPCR) and IHC. Additionally, molecular dynamics simulation (MDS) was employed to investigate the binding mode and stability of the NC-CENPE complex. Multi-dimensional analyses indicated that CENPE is significantly overexpressed in CRC tissues, with a standardised mean difference of 1.32, and its expression scores approach 1.0 in malignant regions. CRISPR screening data suggested that CENPE knockout is associated with markedly reduced proliferation of CRC cells. MDS data supported a plausible binding mode between NC and CENPE, with a predicted binding free energy of -8.2 kcal/mol, in which van der Waals interactions constituted a major component of the calculated binding energy. Furthermore, treatment with NC was associated with significant downregulation of CENPE mRNA and protein levels in CRC cells and xenograft models in this study, although these findings require further validation in additional experimental systems. NC exerts anti-colorectal cancer activity through targeting CENPE. This discovery lays a mechanistic foundation for the development of precision therapies based on active TCM ingredients, offering a new direction for CRC treatment.

To summarize the role of endoplasmic reticulum stress (ERS) in the pathogenesis of diabetic retinopathy (DR) and evaluate potential ERS-targeted interventions.

Soil salinity is a major constraint to crop establishment and yield, particularly during germination and early seedling development of Brassica napus. Here, we report that zinc oxide nanoparticles (ZnONPs) biosynthesized using Pseudomonas aeruginosa alleviate salinity stress through coordinated physiological, biochemical, and molecular mechanisms. Comprehensive physicochemical analyses confirmed the formation of hexagonal wurtzite ZnONPs with a plate-like morphology (thickness ~ 54.5 nm) and an optical band gap of 3.01 eV. Canola seeds were primed with ZnONPs (25-100 mg L⁻¹) under control or 150 mM NaCl stress and subsequently grown in hydroponics. Salt stress reduced germination (41%), biomass, and vigor, while elevating lipid peroxidation and reactive oxygen species. ZnONPs, particularly at 50 mg L⁻¹, restored germination to control levels, enhanced shoot (52 cm) and root (35 cm) elongation, and nearly doubled salt-stressed biomass. ZnONP treatment suppressed malondialdehyde and H₂O₂ accumulation below control values, while up-regulating superoxide dismutase and catalase activity. Furthermore, ZnONPs reduced osmolyte (proline and glycine betaine) accumulation, increased chlorophyll content, lowered Na⁺, and elevated K⁺ and Zn uptake, thereby improving ion homeostasis. Transcript analysis revealed that salinity strongly induced the stress-responsive kinase BnSRK2D (~ 86-fold) and repressed auxin-responsive genes, whereas 50 mg L⁻¹ ZnONPs normalized these responses, down-modulating stress signaling and restoring auxin pathways. Collectively, these findings demonstrate that biogenic ZnONPs mitigate salinity stress in B. napus through integrated regulation of antioxidant defense, ion balance, and hormone-mediated gene expression, highlighting their potential as sustainable nanopriming agents for crop improvement under saline conditions.

Capecitabine has been commonly used for the treatment of early-stage triple-negative breast cancer (TNBC) patients; however, the resistance limits its curative potential. Here, we perform multi-omics data analysis and immunohistochemical (IHC) staining of biological samples from patients in the CBCSG010 clinical trial who were randomized to receive adjuvant docetaxel-anthracycline-based chemotherapy with or without capecitabine. We find that patients with a better prognosis in the capecitabine group exhibited an immune-inflamed microenvironment and upregulation of interferon pathways. Moreover, we identify interferon-related TANK-binding kinase 1-binding protein 1 (TBKBP1) as the key gene involved in capecitabine resistance. We uncover that TBKBP1 promotes capecitabine resistance through impairment of activated immune cells infiltration in vivo. Mechanistically, TBKBP1 negatively regulates type I interferon pathway activated by capecitabine treatment, by promoting autophagy-mediated protein degradation of TANK binding kinase 1 (TBK1). In summary, our study implicates TBKBP1 in mediating capecitabine resistance and may serve as a potential therapeutic target for the treatment of TNBC.

Medulloblastoma and glioblastoma are the most common malignant primary brain tumors in children and adults, respectively. Tumor-associated macrophages and microglia are key non-cancerous cell types in these tumors. These cells interact with CD24, a so called "don't eat me signal" expressed on tumor cells, through Siglec-10, a receptor that contributes to immune evasion by promoting an immunosuppressive environment. The CD24/Siglec-10 interaction in context of malignant brain tumors has been scarcely studied.In silico analyses reveal that CD24 gene expression correlates with specific gene signatures associated with prognosis in both medulloblastoma and glioblastoma. In both human- and mouse brain tumors, Siglec-10+ cells co-express the microglia-associated molecule TREM2. Treatment with mitoxantrone as an immunogenic cell-death-inducing cytostatic agent led to a dose-dependent reduction in cell viability and cell surface CD24 levels in both murine and human brain tumor cell cultures. Intratumoral mitoxantrone administration in a murine CD24-high glioma model extended survival, decreased tumor size, reduced Siglec-10+/TREM2+ cell populations, and increased anti-tumor CD8+ cells. These findings suggest that targeting the CD24/Siglec-10 axis with mitoxantrone may modulate the tumor microenvironment and enhance anti-tumor immunity. Keywords: CD24, Siglec-10, Mitoxantrone, Malignant brain tumor, Immunotherapy.

Epigenetic inhibitors exhibit powerful antiproliferative and anticancer activities. However, cellular responses to small-molecule epigenetic inhibition are heterogeneous and dependent on factors such as the genetic background and metabolic state of cells, as well as on-/off-target engagement of individual small-molecule compounds. The molecular study of the extent of this heterogeneity often measures changes in a single cell line. To more comprehensively profile the effects of small-molecule perturbations and their influence on heterogeneous cellular responses, we present a molecular resource based on the quantification of chromatin, proteome, and transcriptome remodeling due to histone deacetylase inhibitors (HDACi) in non-isogenic cell lines. Through quantitative molecular profiling of 10,621 proteins, these data reveal coordinated molecular remodeling of HDACi treated cancer cells. HDACi-regulated proteins differ greatly across cell lines with consistent (JUN, MAP2K3, CDKN1A) and divergent (CCND3, ASF1B, BRD7) cell-state effectors. Together these data provide valuable insight into cell-type driven and heterogeneous responses that must be taken into consideration when monitoring molecular perturbations in culture models. We have also built a web interface for the extensive amount of data to allow users to explore the data as a resource for understanding chemical perturbation of diverse cell types.

The AT-Rich Interaction Domain (ARID) family plays critical roles in malignancies. Although numerous members have been shown to influence cancer processes, there is a lack of a general understanding of the ARID family in colon cancer. To address this gap, we used bioinformatic technologies to investigate the role of the ARID family as a whole and to identify the crucial member. Subsequently, cell growth assays, transwell assays, and animal models were employed to validate the key member's effect on colon cancer growth and metastasis. Furthermore, bioinformatics and immunohistochemistry were utilised to explore the potential mechanisms and evaluate the efficacy of a targeted intervention strategy. Our results showed that the ARID family was upregulated in colon cancer, with ARID3A being the main component that promoted colon cancer development. Specifically, ARID3A enhanced colon cancer cell proliferation, migration, and invasion both in vivo and in vitro. Mechanistically, this promotional effect could be associated with ARID3A promoting PGE2 synthesis and triggering macrophage infiltration. Notably, aspirin treatment reduced the PGE2 level, which significantly inhibited the malignant behaviour of ARID3A-overexpressing cells. In conclusion, ARID3A was a key member of the ARID family in the development of colon cancer. ARID3A was an underlying biomarker for aspirin administration.