Lung adenocarcinoma (LUAD) remains the leading cause of cancer-related mortality worldwide, highlighting the urgent need for novel therapeutic targets. While the role of the somatostatin receptor (SSTR) family is well established in neuroendocrine tumors, their expression patterns, clinical significance, and therapeutic potential in LUAD are not fully understood. In this study, comprehensive analyses of publicly available databases, including TCGA, GSCA, and TIMER, revealed that SSTR4 transcriptional expression is significantly downregulated in LUAD tissues compared to adjacent normal lung tissues. Moreover, low SSTR4 expression correlates with advanced tumor stage, remodeling of the immune microenvironment, and decreased overall survival in patients with LUAD. Using the PRESTO-Tango system, we identified tangeretin (TAN) as a potential ligand for SSTR4. Functional assays demonstrated that SSTR4 knockdown markedly enhanced TAN-mediated proliferative, migratory, and survival inhibitory effects in LUAD cells. Subsequent RNA sequencing and pathway enrichment analyses revealed that the loss of SSTR4 altered the effects of TAN from extracellular matrix remodeling to disruption of calcium homeostasis and energy metabolism disorders, elucidating the mechanism underlying the enhanced antitumor activity. Collectively, these findings establish SSTR4 as a critical tumor suppressor and prognostic biomarker in LUAD and highlight the therapeutic potential of targeting the TAN-SSTR4 signaling axis. These results provide novel insights into the biological functions of SSTR family members in LUAD.

Phytosulfokine (PSK) is a tyrosine-sulfated pentapeptide found throughout the plant kingdom, playing key roles in plant growth, development, and responses to biotic and abiotic stresses. However, there is still a lack of a comprehensive analysis of the BnPSK gene family in Brassica napus. In this study, we conducted a genome-wide identification and characterized 19 BnPSK genes in oil seed plants, which are unevenly distributed across both sub-genomes (A and C). BnPSK proteins ranged from 77 to 99 amino acids (BnPSK3c and BnPSK3d) in length, all belonging to the PSK-α type and containing conserved PSK domains. Synteny analysis revealed that the expansion of the BnPSK gene family is primarily attributed to whole genome duplication, with homology to Arabidopsis thaliana PSK genes. A promoter region analysis identified cis-acting elements related to hormone and stress responses. An expression profile analysis showed that BnPSK genes are highly expressed in roots, leaves, petals, and pollens and are induced by both abiotic stresses and phytohormone application. Furthermore, RT-qPCR assay demonstrated that the expression levels of BnPSK4c, BnPSK5a, and BnPSK5b were significantly enhanced under drought stress (3~5-fold) both in plant roots and leaves following ABA application. Lastly, the application of ABA induced antioxidant activity including SOD, POD, CAT and APX (2~5-fold) and their corresponding genes (3~5-fold), and altered the ROS-signaling in rapeseed plants; also, strong evidence of mitigating drought stress was present. These findings establish a basis for further research into the role of the BnPSK gene family in oilseed plant tolerance against drought stress and underlying molecular mechanisms, offering valuable perspectives for developing novel peptides.

DNA methylation regulates plant growth by modulating gene expression; however, its contribution to hormone responsiveness and photomorphogenesis remains only partially understood. We examined Arabidopsis thaliana DNA methylation mutants met1 and drm1, drm2, and cmt3 (ddc) under defined light regimes and following exogenous treatments with auxin, gibberellin, and the auxin transport inhibitor TIBA. Hypocotyl elongation and cotyledon expansion exhibited strong light dependency across all genotypes, with met1 seedlings developing a consistently reduced cotyledon area and ddc seedlings displaying impaired hypocotyl elongation under specific light qualities. Exogenous auxin inhibited growth in all genotypes, whereas GA3 promoted elongation in hypocotyls and roots (by approximately 75-80% and 15-35%, respectively, in Col0 and met1), with ddc exhibiting delayed and non-linear dose-dependent sensitivity. Quantitative RT-PCR analysis revealed differential expression of genes involved in auxin transport (PIN1, PIN3, PIN7), auxin signalling (ARF7, IAA3, LAX3), circadian regulation (TOC1, LHY, CCA1), and light signalling (PIFs, HY5, HYH), supporting a link between DNA methylation status and coordinated regulation of hormone-, light-, and clock-controlled transcriptional networks. Together, these findings demonstrate that MET1- and DRM/CMT-dependent methylation pathways integrate epigenetic regulation with environmental and hormonal cues, modulating the intensity, timing, and organ specificity of growth responses, thereby fine-tuning growth plasticity during early Arabidopsis seedling development.

Rice blast, caused by the fungus Magnaporthe oryzae, is a devastating disease that threatens global food security, causing annual yield losses of 10-30%. Consequently, novel control strategies beyond conventional fungicides are urgently needed. Tetramycin, a polyene macrolide antibiotic, is known for its broad-spectrum antifungal activity. However, the specific mechanisms underlying its efficacy against rice blast remain to be fully elucidated. In this study, we demonstrate that tetramycin confers resistance through a dual mode of action. First, in vitro assays revealed that tetramycin directly inhibits M. oryzae mycelial growth. Second, and more critically, it functions as a potent immune elicitor in Oryza sativa. Transcriptome analysis coupled with physiological assays showed that tetramycin treatment triggers a rapid oxidative burst, characterized by significantly elevated activities of key defense enzymes, including superoxide dismutase, peroxidase, phenylalanine ammonia lyase, and polyphenol oxidase (PPO). This oxidative response is further orchestrated through the simultaneous activation of the jasmonic acid (JA) and salicylic acid (SA) signaling pathways, as evidenced by the distinct upregulation of their respective biosynthetic genes and hormone levels. Collectively, these findings indicate that tetramycin not only acts as a direct fungicide but also primes the rice innate immune system via a synergistic reactive oxygen species-JA-SA signaling network, offering a sustainable strategy for rice blast management.

Osthole is a natural coumarin derivative found in several medicinal plants, including Cnidium monnieri and Angelica pubescens. It has been studied for its various biological properties, such as anti-inflammatory, neuroprotective, osteogenic, cardioprotective, antimicrobial, and antiparasitic effects. Osthole was found to induce Fibroblast growth factor 21 (FGF21) expression. Among the known transcription factors that regulate FGF21 induction, activating transcription factor 4 (ATF4) expression was found to be upregulated by osthole. Additionally, as osthole induced ATF4 downstream gene expression, it was concluded that it activates ATF4 signaling. ATF4 knockdown significantly suppressed osthole-mediated induction of FGF21 expression. These findings suggest that osthole activates FGF21 expression via ATF4 activation.

Forkhead box class O1 (FOXO1) and fas-associated death domain (FADD) regulate cell death pathways and homeostatic processes such as cell cycle progression and apoptosis. FADD phosphorylation promotes nuclear localization of FOXO1, and FOXO1 regulates FADD expression. Therefore, it is plausible that FOXO1 and FADD have synergistic or antagonistic effects on cell cycle regulation and the response to anticancer drug treatment in cancer cells. In the present study, we report that AS1842856-mediated inhibition of FOXO1 reverses anticancer drug-induced cytotoxicity, while FADD knockdown increases anticancer drug-induced cytotoxicity in osteosarcoma (OS). Reversed anticancer drug-induced cytotoxicity was accompanied by G2/M cell cycle arrest and increased expression of p21. The anticancer function of FOXO1 was further supported by the observation that OS cells that express higher basal levels of FOXO1 had increased sensitivity to camptothecin-induced cytotoxicity. FADD knockdown reversed the FOXO1 inhibition-induced increase in p21 expression. The results presented in this study indicate that FOXO1 has a tumor suppressor function, while FADD has a tumor-promoting function in OS following anticancer drug treatment. The experimental approach used in this investigation also indicates that FADD antagonizes the effect of FOXO1 on p21 expression in OS.

Mothers face high depression risks during pregnancy, and untreated depression can harm both mother and baby. Vortioxetine is a novel antidepressant with a multimodal mechanism, unlike traditional ones. However, little is known about its safety and effectiveness in pregnancy due to limited preclinical and clinical data. This study investigated how maternal vortioxetine exposure during pregnancy affects DNA methylation in the brain tissue of mother and offspring rats. It also explored putative structural interactions of vortioxetine through molecular docking with key epigenetic enzymes to provide a hypothesis-generating context. Fifty female Sprague-Dawley rats were screened using a repeated forced-swim paradigm to characterize a passive stress-coping phenotype. They were then mated and randomly assigned to five groups (n = 10 each): vortioxetine at 0.5, 1.0, 2.0 mg/kg/day orally, saline control, and escitalopram (2.6 mg/kg/day orally) as a comparison. Treatments were given throughout pregnancy. On the day of cesarean section (G20), brain tissue was collected from both the mother and fetus. Global 5-mC levels were measured with ELISA (three replicates). The binding affinities and interaction motifs of vortioxetine and escitalopram with TET2, DNMT3A, and DNMT3B were analyzed via molecular docking. Global 5-mC levels in brain tissue did not differ between groups. However, a significant decrease in overall methylation was observed in offspring given the highest dose of vortioxetine (2.0 mg/kg/day). Docking analyses revealed that vortioxetine and escitalopram could bind strongly to TET2 and DNMT3A/3B; the observed reduction in global 5-mC was compatible with the hypothesis of altered de novo methylation pathways. The results show a specific dose threshold for the fetus. Low to moderate maternal exposures were not associated with detectable differences in global 5-mC under the current assay conditions, whereas high exposure was associated with hypomethylation in offspring. These findings underscore the importance of careful dose selection and mechanism validation for vortioxetine.

Nonsteroidal anti-inflammatory drugs (NSAIDs) can exacerbate urticaria and/or angioedema in up to 30% of patients with chronic urticaria (CU), representing a distinct subtype characterized by heightened inflammation and leukotriene-driven pathophysiology. MicroRNAs (miRNAs) are post-transcriptional regulators that modulate immune and inflammatory responses. This study aimed to identify differentially expressed miRNAs (DEMs) according to NSAID hypersensitivity status and to elucidate their molecular networks in CU. Serum miRNA profiles were analyzed in 14 NSAID-exacerbated CU (NECU) and 16 NSAID-tolerant CU (NTCU) patients using an Affymetrix GeneChip® miRNA 4.0 Array. DEMs were identified (fold difference > 1.5, p < 0.05), and validated targets were retrieved from the multiMiR database for network construction and Gene Ontology enrichment analyses. NECU patients exhibited a higher frequency of angioedema and systemic corticosteroid use than NTCU patients. Eight DEMs were identified, including upregulated miR-5001-5p, miR-4270, and miR-6869-5p, and downregulated miR-6511b-5p, miR-2277-5p, and miR-378h in NECU. Network integration revealed AGO2-BTG2-LMNB2, NFIC-ZZZ3, and NUFIP2-GLG1 as central clusters, implicating dysregulation of mRNA decay and inflammatory signaling pathways. Reduced miR-6511b-5p expression may derepress BRG1, enhancing chromatin accessibility for inflammatory and leukotriene-synthetic genes. Distinct miRNA signatures differentiate NECU from NTCU, implying a miR-5001-5p/miR-6511b-5p-mRNA decay axis that links impaired post-transcriptional regulation with leukotriene-driven inflammation in CU. These findings highlight candidate miRNAs as potential biomarkers for disease endotyping and therapeutic stratification.

The targeting of cyclin dependent kinase 8 (CDK8) as a potential strategy for cancer treatment has been of interest since the identification of CDK8 as an oncogene product. In this report, we communicate the results of our continuing investigation into the effects of CDK8 inhibitor on triple-negative breast cancer cell line MDA-MB-468. Here, we demonstrate that inhibition of CDK8 decreases phosphorylation of CDK8 substrates E2 promoter binding factor 1 (E2F1) at serine 375 and signal transducer and activator of transcription 3 (STAT3) at serine 727 in these cells. Additionally, luciferase expression was increased in E2F1-responsive luciferase plasmid-transfected cells. Expression of E2F1 transcription target, the proapoptotic protein p73, was increased, and expression of antiapoptotic protein myeloid cell leukemia sequence 1 (Mcl-1) was decreased in CDK8 inhibitor-treated cells. We also demonstrate that knockdown of STAT3 or disruption of STAT3 function in MDA-MB-468 cells opposes the effects of CDK8 inhibition on Mcl-1. Together, these results suggest that CDK8 inhibitor treatment can modulate the expression of apoptosis-related proteins p73 and Mcl-1 and continues to highlight the potential cooperative effects of E2F1 and STAT3 in the activity of CDK8 inhibitor against MDA-MB-468 triple-negative breast cancer cells.

The emergence of SARS-CoV-2, the etiological agent of COVID-19, has resulted in widespread global infection and millions of deaths. Viral entry is initiated by the interaction between the viral spike (S) protein and the host cell receptor ACE2, followed by TMPRSS2-mediated proteolytic activation that facilitates membrane fusion. Bitter melon (Momordica charantia L., MC), a traditional medicinal and edible plant widely used in tropical Asia, possesses notable anti-inflammatory, antioxidant, antitumor, and hypoglycemic properties. In this study, the ethanol extract of bitter melon (EMC) markedly downregulated ACE2 and TMPRSS2 expression in both in vitro and in vivo models without inducing cytotoxicity. Furthermore, phytochemicals isolated from EMC-including p-coumaric acid, rutin, and quercetin-exhibited comparable inhibitory effects. These results indicate that EMC and its bioactive constituents may interfere with SARS-CoV-2 entry by modulating the ACE2/TMPRSS2 axis, highlighting their potential as natural adjuncts for COVID-19 prevention or management.

Ovarian cancer (OC), the third most common gynecologic malignancy, is characterized by high mortality largely driven by chemotherapy resistance, leading to recurrence and metastasis. Using transcriptomic data from GSE73935, we constructed a weighted gene co-expression network and identified eight hub genes (IGF1R, CDH2, PDGFRA, CDKN1A, SHC1, SPP1, CAV1 and FGF18) associated with cisplatin resistance, among which CDH2 emerged as the most clinically relevant candidate. CDH2 demonstrated moderate diagnostic potential (AUC = 0.792) and was markedly upregulated in cisplatin-resistant A2780/CP70 cells. Independent validation using clinical single-cell RNA-seq data (GSE211956) confirmed its selective enrichment in resistant tumor cell subpopulations. Gene set enrichment analysis linked elevated CDH2 expression to p53 signaling, DNA replication, nucleotide excision repair, and Toll-like receptor pathways, with qPCR supporting upregulation of key downstream genes in resistant cells. Immune deconvolution further indicated that high CDH2 expression correlated with increased infiltration of NK cells, Tregs, macrophages, and neutrophils, and immunohistochemistry verified CDH2 overexpression in cisplatin-resistant tissues. In addition, virtual screening and drug sensitivity profiling identified several FDA-approved agents with potential relevance to CDH2-associated drug response. These findings indicate that CDH2 may serve as a candidate marker associated with cisplatin response in OC, and its association with immune cell infiltration provides further insight into mechanisms potentially underlying chemoresistance.

The proper course of pregnancy and fetal development depends, among other factors, on maintaining adequate levels of micronutrients in the maternal body. This integrative, concept-driven narrative review summarizes the current state of knowledge on the impact of selected elements, referred to as oncoelements, on placental function and obstetric outcomes. These include both potentially protective elements (selenium, zinc, copper) and toxic metals (cadmium, lead, arsenic), which, in excess may disrupt oxidative, hormonal, and epigenetic homeostasis. Rather than providing a quantitative synthesis, the article is structured around a four-level conceptual model integrating molecular mechanisms, placental protection, clinical outcomes, and umbilical cord blood as a biomarker of prenatal exposure. Mechanisms of toxicity include oxidative stress, mitochondrial dysfunction, DNA damage, and altered gene expression. Given the observational nature of most studies, clinical recommendations remain cautious. Micronutrient assessment may be useful in selected high-risk groups, but requires further validation. In environmentally burdened regions, screening for toxic metals may be considered. Future research should clarify dose-response relationships, define threshold concentrations, and explore molecular biomarkers of exposure. Umbilical cord blood offers a promising matrix for assessing fetal exposure, although interpretation is limited by methodological variability and the lack of reference values.

Thyroid hormones (THs) regulate metabolism, proliferation, and genomic stability. Clinical studies have linked levothyroxine therapy with higher Oncotype DX Recurrence Scores in breast cancer (BC), suggesting a potential effect of thyroid hormone signaling on genomic risk. Here, we investigated the impact of triiodothyronine (T3) on DNA damage and repair pathways in estrogen receptor-positive T47D breast cancer and non-tumorigenic MCF10A cells. RNA sequencing revealed significant upregulation of RAD51 and enrichment of DNA repair pathways following 24 h T3 exposure. Consistently, T3 increased γH2AX and 53BP1 nuclear foci, indicating transient activation of the DNA damage response (DDR). These effects were transient, returning to baseline after 48 h, suggesting cellular adaptation. T3 also enhanced proliferation at 10 μM but inhibited growth at higher concentrations. Our findings indicate that acute exposure to T3 induces transient genomic stress, providing a potential mechanistic basis for the observed association between thyroid hormone therapy and increased BC recurrence risk.

Colorectal cancer is one of the leading causes of cancer-associated mortality, and multifactorial resistance remains one of the main challenges in its treatment. Essential oils and their main compounds show interesting anticancer properties, but their mechanism of action is yet to be defined. This study aims to assess the cytotoxic effects of eugenol (EU) and cinnamaldehyde (CN) on colorectal cancer (CRC) cells, highlighting possible mechanisms of action. These compounds were tested on normal immortalized colonocytes (NCM-460) and two CRC cell lines: Caco-2, a human colon epithelial adenocarcinoma cell line, and SW-620, colon cancer cells derived from a lymph node metastatic site. The efficacy of EU and CN was evaluated through CellTiter-Glo® and clonogenic assays and by determining proinflammatory cytokine secretion. Transcriptome analysis was used to identify possible pathways affected by EU and CN treatments. The results confirmed that EU and CN were selectively cytotoxic and pro-apoptotic against CRC cells, with different putative mechanisms. While EU drove cytotoxicity through robust transcriptional remodeling, CN yielded a stronger anti-inflammatory action. We confirmed that EU and CN are promising natural candidates in CRC prevention and treatment, even in association with chemotherapeutic drugs.

Acrolein, a highly reactive environmental toxicant widely present in urban air and tobacco smoke, has been implicated in the development of multiple malignancies. In oral tissues, chronic acrolein exposure induces oxidative stress, inflammation, and genetic mutations, all of which are closely linked to the development of oral squamous cell carcinoma (OSCC). Although accumulating evidence indicates a strong association between acrolein exposure and OSCC, its prognostic significance remains poorly understood. In this study, we analyzed transcriptome data to identify differentially expressed genes (DEGs) between tumor and adjacent normal tissues, and screened acrolein-related candidates by intersecting DEGs with previously identified acrolein-associated gene sets. Functional alterations of these genes were assessed using Gene Set Variation Analysis (GSVA), and a protein-protein interaction (PPI) network was constructed to identify key regulatory genes. A prognostic model was developed using Support Vector Machine-Recursive Feature Elimination (SVM-RFE) combined with LASSO-Cox regression and validated in an independent external cohort. Among the acrolein-related DEGs, four key genes (PLK1, AURKA, CTLA4, and PPARG) were ultimately selected for model construction. Kaplan-Meier analysis showed significantly worse overall survival in the high-risk group (p < 0.0001). Receiver operating characteristic (ROC) curve analysis further confirmed the strong predictive performance of the model, with area under the curve (AUC) values of 0.72 at 1 year, 0.72 at 3 years, and 0.75 at 5 years. Furthermore, the high risk score was significantly correlated with a 'cold' immune microenviroment, suggesting that acrolein-related genes may modulate the tumor immune microenvironment. Collectively, these findings highlight the role of acrolein in OSCC progression, suggesting the importance of reducing acrolein exposure for cancer prevention and public health, and call for increased attention to the relationship between environmental toxicants and disease initiation, providing a scientific basis for public health interventions and cancer prevention strategies.

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have revolutionized the management of type 2 diabetes mellitus, heart failure, and chronic kidney disease (CKD), providing cardiorenal and metabolic benefits that extend beyond glycemic control. While their clinical efficacy is well established, the underlying molecular mechanisms remain only partially understood. This review focuses on current knowledge of SGLT2 expression and regulation in health and metabolic diseases, as well as transcriptional and epigenetic consequences of pharmacological SGLT2 inhibition. Human and experimental studies demonstrate that SGLT2 expression is confined to proximal tubular cells and regulated by insulin, the renin-angiotensin-aldosterone system, the sympathetic nervous system, oxidative stress, and transcriptional and epigenetic pathways. SGLT2 expression follows a biphasic pattern in metabolic disorder-associated CKD: upregulation in early phases and reduction in advanced stages. Evidence from animal models and single-cell transcriptomic studies indicates that SGLT2is normalize metabolic and inflammatory gene networks. To our knowledge, a recent single-cell RNA sequencing study provides the only currently available human dataset linking SGLT2i therapy with tubular metabolic rewiring and suppression of the energy-sensitive mechanistic target of rapamycin complex 1. Collectively, these findings support a model in which SGLT2 inhibition mitigates metabolic stress by restoring energy homeostasis across multiple nephron segments.

Background: This study systematically investigates the therapeutic effects of naringenin (NAR) and oleuropein (OLE) on prostate cancer through miR-155-5p regulation. Methods: Experimental studies conducted on MAT-LyLu prostate cancer cell lines revealed that the application of NAR (50 μM) and OLE (75 μM) significantly increased miR-155-5p expression by 2.89-fold and 1.74-fold, respectively (p < 0.05). Bioinformatics analyses have indicated that miR-155-5p interacts with critical oncogenic pathways such as KRAS, CDK2, NF-κB, and TGF-β/Smad2. Computational analyses have revealed that miR-155-5p interacts with 16 critical oncogenic targets, including KRAS and CDK2. Molecular docking studies showed that NAR binds to the Switch I/II region of KRAS with a binding energy of -8.2 kcal/mol, while OLE binds to the ATP-binding pocket of CDK2 with an affinity of -9.1 kcal/mol. Pharmacokinetic evaluations revealed that NAR indicated high oral bioavailability (93.763% HIA) and full compliance with Lipinski's rules, while OLE required advanced formulation strategies due to its high polarity. Network pharmacology analyses have shown that NAR affects lysosomal functions and enzyme regulation, while OLE affects G protein-coupled receptors and oxidoreductase activity. Results: Results indicate that NAR and OLE exhibit antitumor effects through multiple mechanisms by increasing miR-155-5p expression and inhibiting critical oncogenic targets in prostate cancer. Conclusions: Findings suggest that the dietary intake of these natural compounds (citrus and olive products) should be considered in prostate cancer prevention strategies, shedding light on the epigenetic mechanisms of polyphenols in cancer treatment and contributing to the development of new therapeutic strategies.

Recurrent endometrial cancer (EC) has limited therapeutic options beyond platinum-based chemotherapy, highlighting the need to identify exploitable molecular vulnerabilities. Tumors with high genomic instability, including microsatellite instability-high (MSI-h) or copy-number-high (CNH) ECs, rely on the ATR-CHK1 signaling pathway to tolerate replication stress and maintain genome integrity, making this pathway an attractive therapeutic target. However, acquired resistance to ATR and CHK1 inhibitors (ATRi/CHK1i) often develops, and the transcriptomic basis of this resistance in EC remains unknown. Here, we established isogenic ATRi- and CHK1i-resistant cell line models from MSI-h (HEC1A) and CNH (ARK2) EC lineages and performed baseline transcriptomic profiling to characterize stable resistance-associated states. MSI-h-derived resistant clones adopted a unified transcriptional state enriched for epithelial-mesenchymal transition, cytokine signaling, and interferon responses, while ATRi-resistant models showing additional enrichment of developmental and KRAS/Notch-associated pathways. In contrast, CNH-derived resistant clones diverged by inhibitor class, with ATRi resistance preferentially enriching proliferation-associated pathways and CHK1i resistance inducing interferon signaling. Notably, THBS1, EDN1, and TENM2 were consistently upregulated across all resistant models relative to parental lines. Together, these findings demonstrate that acquired resistance to ATRi and CHK1i in EC is shaped by both lineage and inhibitor class and provide a transcriptomic framework that may inform future biomarker development and therapeutic strategies.

Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) are characterized by complex pathologies with progressive neurodegeneration, protein misfolding, oxidative stress, and persistent inflammation. Recent findings indicate the pivotal involvement of epigenetic disruption, particularly aberrant histone deacetylase (HDAC) activity, in disease initiation and progression. In the current review, we systematically discuss the mechanistic function of HDACs across all classes (I, IIa, IIb, III, and IV) in neurodegenerative disease mechanisms, such as their involvement in the modulation of gene expression, mitochondrial function, proteostasis, and neuronal survival. We discuss the therapeutic potential, as well as limitations, of HDAC inhibitors (HDACis), such as pan-inhibitors and isoenzyme-selective inhibitors, and new multi-target-directed ligands with HDAC inhibition combined with acetylcholinesterase modulation, PDE modulation, MAO-B inhibition, or NMDAR modulation. Particular emphasis is placed on the development of HDAC6-selective inhibitors with enhanced brain permeability and reduced toxicity, which have shown promising preclinical efficacy in ameliorating hallmark pathologies of AD, PD, and HD. In addition, s-triazine-based scaffolds have recently emerged as promising chemotypes in HDAC inhibitor design, offering favorable pharmacokinetic profiles, metabolic stability, and the potential for dual-target modulation relevant to neurodegeneration. The review also explores the future of HDAC-targeted therapies, including PROTAC degraders, dual-inhibitor scaffolds, and sustainable, BBB-penetrant molecules. Collectively, this review underscores the importance of HDAC modulation as a multifaceted strategy in the treatment of neurodegenerative diseases and highlights the need for continued innovation in epigenetic drug design.

Zinc (Zn) is a mineral micronutrient that is essential for plant growth and development. Soil Zn deficiency or excess severely impacts plant health and crop yields. MicroRNAs (miRNAs) play crucial roles in plant responses to abiotic stress, but their roles in Zn homeostasis in important crop bread wheat (Triticum aestivum L.) remain unknown. This study investigated miRNA expression profiles in wheat roots under different Zn supply conditions using high-throughput sequencing. Phenotypic and physiological analyses revealed that high Zn promoted wheat plant growth, while low and excess Zn resulted in wheat plant growth inhibition and oxidative stress. A total of 798 miRNAs (including 70 known and 728 novel miRNAs) were identified; among them, 10 known and 122 novel miRNAs were differentially expressed. Many key miRNAs, such as miR397-5p, miR398, 4D_25791, and 5A_27668, are up-regulated under low Zn but down-regulated under high Zn and excess Zn. Target gene prediction and enrichment analysis revealed that the regulated genes of these miRNAs focused on "zinc ion transmembrane transporter activity", "divalent inorganic cation transmembrane transporter activity", and "cellular detoxification" processes in the low Zn vs. CK group. However, "glutathione metabolism" and "ABC transporter" pathways were obviously enriched in high Zn vs. excess Zn conditions, implying their potential functions in alleviating the oxidative damage and Zn efflux caused by Zn toxicity. Together, this study identified key miRNAs that respond to both Zn deficiency and excess Zn in bread wheat, revealing distinct regulatory patterns of the target genes in different Zn supply conditions. These findings provide a new field and valuable candidate miRNAs for molecular breeding aimed at improving zinc's utilization efficiency in wheat.