Pseudomonas aeruginosa is an opportunistic Gram-negative pathogen for which new antimicrobial strategies are urgently needed. To facilitate the establishment of the infection, P. aeruginosa produces a remarkable assortment of both cell-associated and extracellular virulence factors. The expression of numerous virulence traits is regulated by the pqs quorum sensing (QS) system, which relies on multiple enzymes for the biosynthesis of 2-alkyl-4-quinolone (AQ) signal molecules and on the transcriptional regulator PqsR, whose activity is triggered by AQ binding. Herein, we report on the design and synthesis of novel quinazolinone-based PqsR modulators, which led to the identification of two novel compounds endowed with anti-PqsR activity in the submicromolar range. Additionally, these derivatives inhibited the production of PqsR-controlled virulence factors in laboratory strains and clinical isolates of P. aeruginosa.

Non-small cell lung cancer (NSCLC) treatment faces significant challenges due to drug resistance and toxicity. Emerging evidence suggests that ferroptosis, an iron-dependent form of regulated cell death, is a promising therapeutic strategy. We identify Pinostilbene, a natural stilbenoid, as a potent and novel STING agonist. Our findings reveal that Pinostilbene effectively activates the STING/TBK1/IRF3 pathway, leading to the transcriptional upregulation of downstream cytokines. Importantly, we demonstrate that Pinostilbene significantly enhances the sensitivity of lung cancer cells to RSL3-induced ferroptosis. Mechanistically, Pinostilbene promotes the degradation of the iron-storage protein Ferritin Heavy Chain 1 (FTH1), a key negative regulator of ferroptosis. We uncover a novel mechanism in which Pinostilbene induces FTH1 degradation through the ubiquitin-proteasome system via K48-linked polyubiquitination, a process independent of NCOA4-mediated ferritinophagy. This FTH1 degradation increases the labile iron pool, a critical prerequisite for ferroptosis. In vivo, Pinostilbene exhibits robust antitumor efficacy alone and achieves synergistic tumor growth inhibition when combined with RSL3 in a NSCLC mouse model without systemic toxicity. Its therapeutic effect is linked to STING activation and FTH1 downregulation, which coincides with an increase in the ferroptosis biomarker 4-HNE. Furthermore, Pinostilbene enhances antitumor immunity by upregulating inflammatory cytokines and promoting the infiltration and activation of tumor-killing CD8+ T cells, alongside drving anti-tumor M1 polarization of macrophages. Our study highlights the potential of Pinostilbene as a promising therapeutic agent for NSCLC, offering a multifaceted mechanism of action through ferroptosis sensitization and immunostimulation.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, primarily due to its highly fibrotic and immunosuppressive tumor microenvironment (TME), which limits both drug delivery and immune cell infiltration. Epigenetic dysregulation plays a pivotal role in shaping these barriers by controlling transcriptional programs that govern tumor-immune interactions, stromal remodeling, and immune evasion.This review synthesizes current insights into the contribution of aberrant epigenetic mechanisms to PDAC progression and immune resistance. We outline how epigenetic alterations suppress antigen presentation, sustain immunosuppressive cell populations, such as regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages, and upregulate immune checkpoint molecules across cancer and stromal compartments. Emerging evidence shows that epigenetic therapies targeting DNA methyltransferases, histone deacetylases, histone methyltransferases, or bromodomain proteins can restore tumor immunogenicity, reprogram cancer-associated fibroblasts, and promote cytotoxic T cell infiltration. Furthermore, combining epigenetic modulators with immune checkpoint blockade or targeted therapies has demonstrated the capacity to remodel the PDAC TME and convert immunologically 'cold' tumors into more responsive ones. Therefore, we also summarize key completed and ongoing clinical trials in PDAC and solid tumors, emphasizing outcomes and biomarker discoveries that support the translation of epigenetic-immunotherapy combinations into clinical practice. Finally, we discuss persistent challenges that impede progress, including poor drug penetration through the desmoplastic stroma, off-target effects and toxicity of epigenetic agents, tumor hypoxia, adaptive resistance, and the scarcity of physiologically relevant immuno-oncology models.Findings from preclinical and early clinical studies indicate that epigenetic reprogramming represents a promising avenue to overcome PDAC immunoresistance by reactivating antigen presentation, disrupting immunosuppressive cellular networks, and enhancing antitumor immunity. However, realizing this potential will require rationally designed combination regimens, predictive biomarkers for patient stratification, and a deeper understanding of cell type-specific and context-dependent epigenetic regulation. Only through these advances can the integration of epigenetic modulation with immunotherapy and stroma-targeting approaches ultimately redefine therapeutic strategies for patients with PDAC.

Osimertinib resistance remains a major challenge in the treatment of non-small cell lung cancer (NSCLC). Cancer-associated fibroblasts (CAFs) are the most abundant stromal cells in tumor microenvironment (TME), however, its role in osimertinib resistance in NSCLC is not fully understood. In this study, it was found that CAFs promoted osimertinib resistance in NSCLC cells via elevating RNA m7G modification. Methyltransferase 1 (METTL1) in NSCLC cells mediated CAFs' effect on m7G modification, and METTL1 was associated with NSCLC progression and poor prognosis. Further study demonstrates that CAFs upregulated METTL1 in NSCLC cells by secreting HMGB1. By applying MeRIP-seq and RNA-seq, neuroepithelial cell transforming gene 1 (NET1) was identified as a target of METTL1, and enhanced m7G modification of NET1 increased NET1 expression and activated downstream AKT/NF-κB pathway. Importantly, reducing m7G modification by METTL1 knockdown significantly attenuated CAFs' stimulatory effect on osimertinib resistance both in vitro and in vivo. Our study revealed a novel mechanism that CAFs conferred osimertinib resistance in NSCLC cells through modulating m7G modification. These findings underscore the importance of m7G modification in the communication between cancer cells and the TME, and pave the way for finding novel therapeutic strategies to overcome drug resistance by targeting m7G modification.

Despite the transformative impact of osimertinib as a cornerstone targeted therapy for advanced EGFR-mutant non-small cell lung cancer, the emergence of acquired resistance ultimately limits its long-term efficacy. While genetic alterations, tumor microenvironment dynamics, and cancer stem cells contribute to resistance, they inadequately explain its rapid adaptive evolution. This critical knowledge gap points to an underexplored dimension of resistance: the dynamic reprogramming of the epigenetic landscape. This review establishes dynamic histone plasticity--driven by imbalances in key epigenetic modifications such as acetylation and methylation, along with newly recognized marks including lactylation--as a pivotal epigenetic driver of resistance. Evidence demonstrates that these modifications remodel chromatin architecture, reprogram transcriptional networks, compromise DNA damage repair, and stabilize a drug-tolerant persister state, collectively accelerating tumor adaptation during therapeutic pressure. Beyond mechanism, distinct histone-modification signatures are emerging as promising predictive biomarkers for resistance, simultaneously revealing novel, pharmacologically targetable epigenetic vulnerabilities. Leveraging next-generation technologies, we propose an integrated strategy: multimodal epigenetic therapies combined with real-time liquid biopsy profiling to shift from reactive management toward predictive prevention of resistance. By bridging deep epigenomic mechanistic understanding with innovative diagnostic and therapeutic tools, this roadmap provides a proactive, adaptive framework designed to circumvent tumor evolutionary pathways, overcome therapeutic resistance, and prolong patient survival.

Nanoplastics are emerging environmental pollutants ubiquitously found in natural ecosystems. Although studies have shown that nanoplastics can accumulate in the testes of mice and affect spermatogenic cells, the specific toxicological mechanisms remain unclear. To investigate the specific mechanism by which polystyrene nanoplastics induce ferroptosis in mouse spermatocyte-derived GC-2spd(ts) cells and subsequently lead to male reproductive toxicity, this study exposed mouse germ cell lines (GC-1 spg and GC-2spd(ts)) to PS-NPs of two sizes (50 nm and 90 nm). Cell viability assays indicated that GC-2spd(ts) cells were more sensitive to PS-NPs exposure. Transcriptomic and proteomic analyses revealed that PS-NPs exposure induced intracellular reactive oxygen species (ROS) accumulation and significant alterations in related pathways, specifically activating the ferroptosis signaling pathway. Further mechanistic studies demonstrated that PS-NPs disrupted intracellular iron homeostasis, leading to the accumulation of labile Fe2+ , enhanced lipid peroxidation, depletion of the antioxidant glutathione, and mitochondrial dysfunction. At the molecular level, PS-NPs upregulated the expression of iron uptake-related proteins and significantly downregulated the iron exporter protein ferroportin1 (FPN1). In-depth investigation revealed that PS-NPs did not affect the transcriptional level of FPN1 but promoted FPN1 protein degradation by enhancing its ubiquitination modification, subsequently via the proteasome-dependent pathway. This process resulted in blocked cellular iron efflux, iron ion accumulation, and ultimately triggered ferroptosis. This study elucidates the molecular mechanism by which PS-NPs regulate FPN1 degradation through the ubiquitin-proteasome pathway, disrupt iron metabolic homeostasis, and thereby induce ferroptosis in germ cells, providing novel experimental evidence for assessing the male reproductive toxicity of nanoplastics.

The hypothalamic-pituitary-interrenal (HPI) axis mediates stress responses in fish. Previous work showed that dietary supplementation with B vitamins attenuated cortisol response to acute stress, whereas dietary genistein produced high basal levels of cortisol and altered stress responsiveness. In the present study, we investigated the expression of key genes of the HPI axis and selected hepatic targets to better characterize these responses. Cortisol was correlated with nr3c1 expression in the pituitary of control fish. Conversely, B vitamins supplementation was associated with changes in the relationship between plasma cortisol levels and nr3c1 expression across tissues, including higher basal higher basal expression expression in the head kidney. In parallel, lower hepatic oxidative stress following acute stress in this fish was associated with differences in cortisol levels and liver metabolic responses. Dietary genistein was associated with altered pituitary regulation of pomc paralogs, characterized by reduced pomcb and elevated pomca expression after stress. These expression patterns persisted 4.5 months after dietary exposure, with pomca becoming the only gene showing a positive association with plasma cortisol levels. In addition, genistein supplementation was associated with higher basal expression of the ACTH receptor (mc2r) in the head kidney. Stress challenges performed up to one year after the nutritional intervention revealed convergence of cortisol responses among dietary groups. Overall, these results indicate that dietary components can produce short-term changes in the regulation of the HPI axis. Further studies are required to clarify the mechanisms underlying the dietary effects observed in this study.

Nanoencapsulation, especially in the form of PEGylated niosomes, is considered a novel strategy in drug delivery that improves the solubility and bioavailability of compounds. Silibinin, as a flavonoid, has low bioavailability despite its antioxidant, anti-inflammatory, and neuroprotective properties. Therefore, the present study was designed to investigate the effect of PEGylated niosomal nanoparticles containing Silibinin (Sili-PEG-Nios-NPs) on memory and learning, inflammatory pathways, and morphological changes in the hippocampus in an animal model of Alzheimer's disease. In this study, Sili-PEG-Nios-NPs were synthesized and characterized, followed by Alzheimer's induction in rats via intraventricular Aβ1-42 injection. Rats were divided into five groups (n = 8): a healthy control group, an Alzheimer's model group, a sham group (Alzheimer's model + PBS), an Alzheimer's model group + free Silibinin, and an Alzheimer's model group + Sili-PEG-Nios-NPs. Treatments were administered orally (100 mg/kg for 15 days). Cognitive function was assessed using the Morris water maze and shuttle box tests. Tissue analysis included Real-time PCR for inflammasome genes, Congo red staining for amyloid plaques, and cresyl violet staining for hippocampal pyramidal cells. The results demonstrated that both Silibinin formulations (free and nano-encapsulated) significantly improved spatial memory and learning compared to the disease model group. However, Sili-PEG-Nios-NPs were significantly more effective than free Silibinin and also significantly reduced the expression of inflammasome genes, Aβ plaque formation, and hippocampal neuronal cell destruction. These findings suggest that PEGylated Silibinin-loaded niosomal nanoparticles are an effective option for improving Alzheimer's disease complications by modulating the inflammasome pathway and amyloid plaque aggregation.

Radiation-induced lung injury (RILI) is one of the most prevalent complications of thoracic radiotherapy (RT). Lupenone (LUP) is a bioactive compound isolated from Acacia catechul.f. Willci. and is believed to be capable of treating respiratory and lung diseases.

Ligusticum sinense cv. Chuanxiong (Chuanxiong) is threatened by excessive cadmium (Cd), affecting its safety and quality. This study aimed to characterize Cd distribution in Chuanxiong roots (subcellular level) and clarify its key response mechanisms to Cd stress, using ICP-MS, SEM-EDS, and transcriptome analysis. The results showed that Cd was mainly enriched in root cell walls; Cd stress significantly upregulated the activities of polyphenol oxidase (PPO, +11.50 %), cinnamyl alcohol dehydrogenase (CAD, +31.05 %), catechol O-methyltransferase (COMT, +28.28 %), and isocitrate lyase (ICL, +121.93 %) compared with the control; Cd-related genes (NRAMP5, CAX3, YSL7, etc.) and key transcription factors (BHLH162, ERF109, etc.) were markedly upregulated. Furthermore, Chuanxiong roots achieved growth-stress resistance balance (exhibiting hormesis) via the carbon metabolism pathway (the material and energy basis), the sulfur metabolism (the core detoxification pathway), and the phenylpropanoid biosynthesis (structural and chemical defense). This study provides a theoretical basis for developing precise regulatory techniques to reduce heavy metals (HMs) accumulation in medicinal plants, and thus safeguard their quality and safety.

Microplastics, as a novel environmental pollutant, are now widely distributed in agricultural soils globally and pose a threat to plant growth and development. Within apple orchards, the ageing and degradation of agricultural plastic films leads to soil microplastic contamination, inhibiting the growth of apple trees. This study employed apple rootstocks 'M9' and 'B9' alongside the apple cultivar 'Gala3', treating them with polystyrene nanoplastics (PS-NPs) at varying concentrations (0, 5, 10, 20, 40, 80 mg/L). Results indicate that low PS-NP concentrations promote apple seedling growth, whereas high concentrations inhibit root development and growth while reducing antioxidant capacity. Sensitivity to PS-NPs varies among genotypes, with 'M9' exhibiting the lowest sensitivity and 'Gala3' the highest. Based on these phenotypic differences, transcriptomic and metabolomic sequencing was performed on these two cultivars. Integrated transcriptomic-metabolomic analysis revealed that PS-NPs disrupted zeatin metabolic homeostasis by upregulating CKX gene and downregulating UGT73C gene. This accelerated the metabolism of active zeatin (e.g., trans-zeatin) and leading to dihydrozeatin (DHZ) accumulation, thereby impairing the activation capacity of the antioxidant defence system and ultimately exacerbating oxidative damage. These findings establish a foundation for systematic investigation into the molecular mechanisms underlying apple responses to nanoplastics, offering novel perspectives for future crop production and environmental safety.

Mushrooms have been found to be one of the main sources of nutrients to man, but their nutraceutical approach to life science is still being studied. The proposed concept that mushrooms serve both as food and medicine has placed mushrooms as nutraceuticals. Mushrooms have been discovered to be a good source of a variety of nutritional bioactive compounds with numerous health benefits as well as medicinal properties. The aim of this research was to evaluate the modulatory effect of Pleurotus ostreatus extract on Staphylococcus aureus uspA+ gene expression and antibiotic susceptibility. In this study, indigenous P. ostreatus mushroom extract used was screened for its bioactive phytochemical contents. The effect of P. ostreatus extract on uspA+ S. aureus gene expression and antibiotic susceptibility was conducted using reverse transcriptase polymerase chain reaction (RT-PCR) technique and the Kirby-Bauer test method, respectively. Results obtained showed that uspA genes were domicile in S. aureus and were expressed when exposed to sublethal antibiotic concentrations, whereas the presence of P. ostreatus extract inhibit uspA+ S. aureus gene expression. The susceptibility results showed that inhibition zone diameters (IZDs) were found to be in the ranges between 0- and 8-mm diameter for unexposed S. aureus uspA+ genes to mushroom extract, whereas the IZDs increased to about 15 to 20 mm diameter when exposed to mushroom extract. The mushroom bioactive compounds quantitative analysis showed high flavonoid (63.4 ± 3.6 mg/dL), tannins (29.27 ± 1.0 mg/dL) and phenols (22.0 ± 2.7 mg/dL). Based on these research findings, it shows that P. ostreatus extract can serve as a modulating agent that can be used to regulate the expression of uspA+ gene in S. aureus and can optimize the susceptibility enhancement in antibiotic-mediated S. aureus.

Breast cancer (BC) remains a leading cause of cancer-related death among women. There is an urgent need for new therapies with fewer side effects. This study evaluated the anticancer potential of curcumin micro- and nanocapsules on MCF-7 breast cancer cells and explored the underlying molecular mechanisms using bioinformatics analysis.

In Arabidopsis (Arabidopsis thaliana), a family of 5 receptors mediates ethylene responses in roots, with Ethylene Response 1 (ETR1) controlling increases in root hair proliferation and decreases in lateral root formation. To define the ETR1-dependent gene regulatory network (GRN) controlling root development, we profiled the root transcriptome from Col-0 and the etr1-3 gain-of-function and etr1-7 loss-of-function mutants in the presence and absence of ethylene or the ethylene precursor 1-aminocyclopropane-1-carboxylic acid (ACC). We identified 4,522 differentially expressed (DE) transcripts in Col-0 roots that displayed altered abundance in response to ethylene and/or ACC treatment, with larger-magnitude changes induced by ethylene. These included 553 DE transcripts that were ETR1 dependent, defined by a lack of response to treatment with ethylene and/or ACC in ethylene-insensitive etr1-3 and constitutive alteration response in etr1-7 in the presence or absence of treatment relative to time-0 Col-0. These ETR1-dependent transcripts include transcripts from genes associated with ethylene biosynthesis and those encoding transcription factors (TFs). Reporter fusions driven by promoters from ACC OXIDASE 2 (ACO2) and ACO3, which convert ACC to ethylene, were regulated by ACC in root tissues in appropriate locations to control root development, with pACO5-driven GFP detected in root hairs. We examined the abundance of ETR1-dependent transcripts predicted to encode TFs and ACOs in Col-0 and an ein3 eil1 mutant, with and without ACC treatment. Our results suggested that the ETR1 and Ethylene Insensitive 3 (EIN3)/EIN3-like 1 (EIL1) canonical ethylene signaling pathway regulates some, but not all, of these transcriptional responses. Together, these findings reveal features of an ETR1-dependent GRN that controls both ethylene biosynthesis and root growth and development.

Plants reprogramme their metabolism upon pathogen attack, producing compounds that can either enhance immunity or be exploited by pathogens. Metabolomic profiling of wheat during Fusarium graminearum infection revealed pronounced accumulation of phenolamides, driven by activation of their biosynthetic pathways. Notably, exogenous N-feruloylputrescine (Ferput), a representative phenolamide, enhanced resistance to wheat stripe rust, powdery mildew and rice blast but increased susceptibility to Fusarium head blight. Ferput inhibited fungal infection in the lemma while promoting rachis colonisation, indicating pathogen- and tissue-specific effects. Mechanistic analyses showed that Ferput stimulates deoxynivalenol (DON) biosynthesis by inducing TRI gene expression, toxisome formation and DON-associated cellular differentiation, underlying the shift from lemma resistance to rachis susceptibility. Together, these findings highlight the context-dependent roles of phenolamide in plant-pathogen interactions and suggest that, under specific pathological contexts, defence-associated metabolites can be exploited by pathogens to enhance their virulence. This insight underscores the necessity of considering the dual functional roles of plant metabolites when engineering broad-spectrum disease resistance.

This study profiled physiological, biochemical, and transcriptional responses of Solanum nigrum to cadmium (Cd) in potted soil across graded treatments. Growth, assessed as fresh and dry mass, and chlorophyll a declined only at higher doses, whereas carotenoids increased by about 70%. Proline rose by roughly 302% and soluble proteins by 173% in a dose-responsive manner, consistent with up to 9.1-fold increases in P5CS transcripts. Malondialdehyde and hydrogen peroxide increased with Cd, accompanied by antioxidant responses. Shoots accumulated substantial Cd in soil, reaching 170 mg kg-1 DW at 100 mg kg-1 soil Cd, while the tolerance index remained ≥ 60% at the highest dose. The translocation factor exceeded one at all additions and peaked at ~ 1.28 at 50-100 mg kg-1Bioavailability-aware enrichment remained high: BCF_available (shoot) referenced to DTPA-Cd was ~ 19.4 at 12.5-25 mg kg-1 16.9 at 50 mg kg-1, and 12.6 at 100 mg kg-1. Whole-plant removal increased monotonically, with total Cd uptake of approximately 166, 303, 392, and 518 µg plant-1 at 12.5, 25, 50, and 100 mg kg-1, respectively. Candidate transporter transcripts showed distinct dose-dependent patterns in soil: SnYSL3 peaked at the intermediate dose (~ 7.6-fold), whereas HMA3 rose progressively and was highest at 100 mg kg-1 (~ 7.2-fold). Principal component analysis separated treatments and grouped stress markers with P5CS and HMA3 at higher Cd. This work provides a gradient-resolved, soil-based dataset linking Cd partitioning, bioavailability-normalized indices, and total uptake with coordinated shifts in candidate YSL and HMA transporters and key metabolites. The resulting framework establishes a standardized baseline for functional validation and field translation.

Armillaria species have attracted considerable research interest, because they are widely distributed, mostly plant-pathogenic, and exhibit unique characteristics. Abiotic factors influence intra- and interspecies variations in pathogenicity and/or virulence of these fungi. However, the mechanisms involved in causing these variations are not well understood. Iron is an indispensable element in several molecular and biological processes. Yet, excessive abundance of iron can be toxic to organisms due to Fenton-like reactions. This study aimed to gain insights into the type and extent of iron-responsive proteomic and secretomic changes in Armillaria sp. strain CMW4456 cultured in liquid media supplemented with iron using a multiomics approach. Significant iron-dependent alterations of proteins involved in metabolism and growth were observed in the proteomes and secretomes. Iron supplementation at 100 μM did not elicit an oxidative stress response by the fungus. Our analyses revealed three putative siderophore biosynthetic gene clusters (BGCs) in the genome and expression of proteins encoded by some BGC genes in the proteome. This knowledge contributes to a better understanding of the mechanisms employed by an Armillaria sp. in response to iron, gives insights into possible modes for inhibiting or attenuating the pathogenicity and/or virulence of Armillaria spp., and can be valorized for more biotechnological applications.

Breast cancer is the most commonly diagnosed cancer in women globally. Our previous MIRACLE trial (NCT02313051) demonstrated that everolimus plus letrozole (E + L) significantly improves progression-free survival compared with letrozole (L) monotherapy in premenopausal patients with endocrine therapy-resistant, hormone receptor-positive, HER2-non-amplified advanced breast cancer. This study aims to investigate spatially resolved biomarkers linked to survival benefits from E + L to guide precision therapies. Patients from MIRACLE were stratified by overall survival (OS ≤ 3 vs. >3 years). Spatial Whole Transcriptome Atlas analysis was used to evaluate tumor-, immune-, and stroma-specific gene expression, co-expression network patterns, and survival correlations. Among patients with shorter survival (OS ≤ 3 years), we identified a distinctive gene interaction network characterized by tumor-derived S100A9 and CALML5, which is associated with mTORC1 activation. This finding suggests that tasquinimod, an S100A9 inhibitor, could be a viable therapeutic option. Additionally, an interaction between CALML5 and SLPI across tumor and immune areas indicated a potential role in maintaining tumor integrity and mitigating immune-mediated damage. Conversely, patients with longer survival (OS > 3 years) exhibited SERPINA1 as a hub gene linked to estrogen receptor activation, and an interaction between FKBP5 and SESN3 associated with AKT/mTORC1 inhibition within tumor-rich regions. Furthermore, the interaction between MMP11 and COL16A1 in stroma-rich regions suggests that cancer-associated fibroblasts may contribute to improved outcomes. Our study underscores the critical role of spatial gene expression analysis in elucidating the tumor microenvironment and its impact on prognosis in patients undergoing E + L treatment, thereby opening new avenues for targeted interventions.

Amblyopia is a neurodevelopmental disorder, and there are no effective treatment methods for adult amblyopia patients due to the decline in synaptic plasticity in visual cortex. Enriched environment (EE) has been shown to enhance synaptic plasticity, which is mediated, at least in part, by epigenetic mechanisms involving histone acetylation. This study aims to investigate whether histone deacetylase (HDAC) inhibitors can replicate the effects of EE on visual cortical plasticity, thereby offering novel therapeutic insights for adult amblyopia. First, we established adult amblyopia mice model, which were then randomized into five groups: untreated amblyopia, standard housing, EE, vehicle, trichostatin A (TSA) groups, with normal mice serving as controls. To evaluate synaptic plasticity in visual cortex, we measured synaptic marker VGLUT2, synaptic ultrastructure and long-term potentiation (LTP). Additionally, biochemical analyses were conducted to measure alterations of HDACs associated with synaptic integrity. Our findings revealed that EE enhanced synaptic plasticity in visual cortex of adult amblyopia mice and was associated with reduced HDAC3 expression. Similarly, the broad HDAC inhibitor TSA, improved synaptic ultrastructure, increased VGLUT2 expression, and potentiated LTP, functionally resembling several key effects of EE. Importantly, TSA targets multiple HDAC isoforms, and the observed reduction in HDAC3 levels is correlated with, but does not establish, a causal role for HDAC3. These results indicate that broad HDAC inhibition can mimic EE-induced plasticity in adult amblyopia, while highlighting the need for selective HDAC3-targeted approaches to determine mechanistic specificity. Overall, our study provides a foundation for developing epigenetic-based strategies to enhance adult visual cortical plasticity.

Fibers are the main economic product of cotton (Gossypium hirsutum). As an ideal model for studying plant cell development, many factors that influence cotton fiber have been revealed. Previous studies have demonstrated the important role of sphingolipids in fiber development through chemical and genetic methods, but the regulatory module by which sphingolipids regulate fiber development remains unclear. Here, we used the sphingolipid biosynthesis inhibitor fumonisin B1 (FB1) and found that it effectively suppressed the expression of an orthologue of the trihelix transcription factor SIP1 clade-like (GhSIL) in upland cotton. Lipid-protein binding assays also revealed that ceramide (t18:0/24:0) and 24-epibrassinolide (BL) bind to GhSIL protein in vitro. GhSIL was preferentially expressed in elongating fibers. The transcriptome and reverse transcription quantitative PCR analysis revealed that the expression of brassinosteroid synthesis genes was significantly decreased in GhSIL downregulated cotton fibers during the fiber elongation stage. Yeast 1-hybrid assay, dual-luciferase (LUC) assay, and chromatin immunoprecipitation (ChIP) assays showed that GhSIL can directly bind to the GT1-box element in the brassinosteroid-6-oxidase 2 (GhBR6OX2) promoter region to enhance its expression. Overexpression of GhSIL and GhBR6OX2 promoted fiber elongation, consistent with the results of exogenous application of BL in cotton ovule culture in vitro. By contrast, suppressing GhSIL and GhBR6OX2 expression inhibited fiber elongation, which was similar to the exogenous application of brassinazole (BRZ). These results illuminated that sphingolipids regulate fiber cell elongation through the GhSIL-GhBR6OX2-brassinolide module, which reveals a node in the molecular mechanism by which sphingolipids regulate plant growth and development.