Ceramide galactosyltransferase (UGT8) is overexpressed in basal-like breast cancer (BC) tumors and is associated with an increased risk of lung metastasis. UGT8 synthesizes galactosylceramide (GalCer), an anti-apoptotic molecule that promotes BC cell survival within the tumor microenvironment and enhances resistance to anticancer drugs. In this study, we aimed to elucidate the molecular mechanisms underlying UGT8 overexpression in BC cells. UGT8 promoter constructs and deletion mutants were generated by PCR. Promoter activity was assessed using a dual-luciferase assay, and key regulatory sequences were identified by electrophoretic mobility shift assay (EMSA). Candidate transcription factors were predicted using the JASPAR database and validated by qPCR, Western blotting, and immunohistochemistry. GalCer levels were measured by thin-layer chromatography (TLC) binding assay, and LHX6-DNA interactions were analyzed by surface plasmon resonance. Apoptotic cells were detected using the Thermo Dead Cell Apoptosis Kit. UGT8 promoter activity was significantly higher in UGT8-positive MDA-MB-231 cells than in UGT8-negative T47D and MCF-7 cells, indicating that UGT8 gene expression is regulated at the transcriptional level. Sequential promoter deletions combined with EMSA localized a key regulatory region (- 1132 to - 1618 bp), termed the UGT8 response element (UGT8RE). In silico analysis identified potential transcription factors, among which the LIM/homeobox protein LHX6 was markedly upregulated in MDA-MB-231 cells. Site-directed mutagenesis of two predicted LHX6 binding sites (LHX6BS1 and LHX6BS2) demonstrated that LHX6BS2 is essential for UGT8 promoter activity. RNAi-mediated inhibition of LHX6 reduced UGT8 expression and GalCer synthesis, thereby sensitizing MDA-MB-231 cells to doxorubicin-induced apoptosis. The LIM/homeobox protein LHX6 may regulate the UGT8 expression in BC cells. Targeting LHX6 decreases UGT8 expression and GalCer synthesis, thereby sensitizing MDA-MB-231 cells to doxorubicin. Given UGT8's role in cell survival and drug resistance, inhibition of LHX6 may represent a promising therapeutic strategy for drug-resistant BC.

Heavy metal-induced stress is an abiotic form of stress that significantly restricts crop yield and quality. This stress affects plants at all stages, but they are particularly vulnerable as seedlings, when it can directly influence later growth and development. Cd2+ is an important heavy metal stressor and negatively influences plant growth. However, the regulation mechanism underlying Cd2+ stress resistance has not been adequately elucidated, especially in major cultivars, which restricts the application of Cd2+ resistance. Here, exogenously applied melatonin (N-acetyl-5-methoxytryptamine) was tested on rice seedlings as a practical solution to enhance the plants' stress tolerance. The modern variety Longjing 203 was used for the experiments due to its extensive cultivation in Heilongjiang Province, China. Seedlings were treated with 50μMol/L CdCl2 and 100μMol/L exogenous melatonin to investigate the molecular mechanism underlying exogenous melatonin's ability to enhance Cd2+ tolerance. The results revealed that Cd2+-induced stress limited growth, while melatonin alleviated the stress-induced damage on seedlings. Specifically, differentially expressed gene (DEGs) analysis showed that the phenylpropanoid biosynthesis pathway was enriched in plants treated with melatonin, which was also verified by qRT-PCR, enriched enzyme activity assays, and molecular docking. Also, the results of lignin content and Cd2+ distribution in subcellular compartments indicated that melatonin promoted lignin accumulation and intercepted Cd2+ into the cell wall, limiting influx into organelles and the cytoplasm. Then, the group of applied melatonin had shown to enhance stress tolerance by reducing DNA damage, as evidenced by the DNA cross-linking, 8-hydroxy-20-deoxyguanine levels, relative density of apurinic sites, and random amplified polymorphic DNA (RAPD) analysis. These findings also revealed that exogenous melatonin relieved cellular damage caused by Cd2+ by reinforcing the cell wall lignin barrier to regulate cellular homeostasis.

Ventral hippocampus (vHPC) CA1 pyramidal neurons send glutamatergic projections to nucleus accumbens (NAc), and this vHPC-NAc circuit mediates cocaine seeking and reward, but it is unclear whether vHPC-NAc neuron properties are modulated by cocaine exposure to drive subsequent behavior. The immediate early gene transcription factor FosB/ΔFosB is induced throughout the brain by cocaine and is critical for cocaine seeking, but its function in vHPC-NAc neurons is not understood. We now show that circuit-specific knockout of FosB/ΔFosB in vHPC-NAc neurons impaired cocaine reward expression and forced abstinence-induced seeking. We also found that vHPC-NAc excitability was decreased by experimenter-administered repeated cocaine and cocaine self-administration, and this cocaine-induced excitability decrease was mediated by ΔFosB expression. To uncover the mechanism of this change in circuit function, we used circuit-specific translating ribosome affinity purification to assess cocaine-induced, FosB/ΔFosB-dependent changes in gene expression in vHPC-NAc. We found that cocaine causes a FosB/ΔFosB-dependent increase in the expression of calreticulin, an endoplasmic reticulum-resident calcium-buffering protein. Calreticulin expression mediated vHPC-NAc excitability and was necessary for cocaine reward. These findings uncover a noncanonical mechanism by which cocaine increases calreticulin in vHPC leading to decreased vHPC-NAc excitability and drives cocaine seeking and reward.

Binding of GLP-1 to its receptor in pancreatic beta cells triggers activation of the cAMP pathway and phosphorylation of CREB, leading to induction of cellular target genes containing CREB binding sites. By contrast with their acute effects on beta cell gene expression, chronic exposure of beta cells to stable GLP-1 analogs like Exendin-4 stimulates sustained expression of beta cell-specific genes, leading to increases in beta cell viability and insulin secretion. In a proteomic screen for transcriptional coregulators that contribute to the transcriptional effects of GLP-1, we identified Med14, the scaffolding subunit of the conserved 30 subunit Mediator complex. Exposure to Exendin-4 and other GLP-1 receptor agonists stimulates sustained phosphorylation of Med14 at Ser983, which corresponds to a conserved PKA recognition site. Mutation of Med14 at Ser983 blocked Exendin-4 effects on cellular gene expression by interfering with CREB-mediated activation of beta cell-specific enhancers. Med14 mutation results in higher alpha-to-beta cell ratios and blunted gene regulation in response to Exendin-4 in Ser983-mutant primary mouse islets. Our work reveals how phosphorylation of a general transcription factor in response to GLP-1 analogs triggers a broad genomic response with salutary effects on beta cell function.

Neonatal hypoxic-ischemic encephalopathy (HIE) is a leading cause of neurological disability and mortality in newborns, with limited therapeutic options beyond hypothermia. Bromodomain and extra-terminal domain (BET) proteins function as epigenetic readers that regulate gene expression by recognizing acetylated lysine residues on histones. Among BET inhibitors, (+)-JQ1 (JQ1) has recently garnered attention due to its potent anti-inflammatory and antioxidant properties. This study aims to investigate the neuroprotective effects of JQ1 and elucidate the underlying mechanisms in the context of HIE brain injury.

Salinity stress severely limits barley (Hordeum vulgare L.) growth and productivity. This study examined the effects of chitosan (Cs), selenium (Se), and chitosan-selenium nanoparticles (Cs-Se NPs) on salt tolerance of two barley cultivars, Mv Initium and Tectus, exposed to 0, 100, and 200 mM NaCl. Salinity reduced plant height, biomass, and chlorophyll content. Foliar application of Cs and especially Cs-Se NPs significantly improved these traits. Cs-Se NPs enhanced proline (PRO) accumulation and activities of ascorbate peroxidase (APX) and catalase (CAT) under salt stress in both cultivars, which supports improved ROS scavenging capacity. The significant upregulation of antioxidant enzyme genes (HvAPX, HvSOD, HvCAT) following Cs-Se NPs treatment under salinity strongly indicates enhanced reactive oxygen species (ROS) detoxification. Key ion homeostasis genes (HvSOS1, HvSOS3, HvNHX1 and HvHKT2) were also upregulated, supporting improved salt stress tolerance. Strong correlations were found between antioxidant activity, chlorophyll content, and growth. These findings suggest that Cs-Se NPs effectively boost barley's physiological and molecular defenses against salinity.

The microsporidium Vairimorpha (Nosema) ceranae is an emerging threat to honey bees (Apis mellifera), known to disrupt gut microbiota and suppress immune responses, potentially contributing to colony losses. Fungal extracts have recently gained interest as sources of bioactive compounds with antimicrobial and immunomodulatory potential. In this study, we explored the effects of different dietary supplements-sugar syrup, HiveAlive™, and a novel Ganoderma australe extract (GanoBee)-on gut bacterial composition and immune-related gene expression in honey bees subjected to experimental exposure to V. ceranae 1 x 104 spores per bee. The GanoBee diet altered the gut microbiota, notably reducing the relative abundance of Rhizobiaceae (Bartonella apis) and increasing Frischella compared to other treatments. While alpha diversity was not significantly affected by diet or exposure to V. ceranae, beta diversity differed significantly in bees fed with GanoBee. Additionally, the expression of the antimicrobial peptide genes abaecin and hymenoptaecin was elevated in both exposed and unexposed bees fed with GanoBee, depending on the sampling day. However, the establishment of V. ceranae infection appeared limited, likely due to low spore viability, and mortality in control bees was higher than expected. The low Vairimorpha ceranae infection levels observed in this study are likely attributable to reduced spore viability caused by storage conditions and/or suboptimal environmental conditions within the laboratory cages. Post hoc analyses indicated that the high viscosity of GanoBee-supplemented diets likely contributed to the elevated bee mortality observed, underscoring a critical limitation of the experimental design related to diet formulation and delivery method. These physical factors complicate the interpretation of treatment efficacy and highlight the importance of optimizing feeding protocols to avoid confounding effects. Despite these constraints, GanoBee demonstrated promising potential as a modulator of gut microbiota composition and immune-related gene expression, supporting the need for further research under improved and carefully controlled experimental conditions.

Members of the genus Streptomyces are major producers of a wide variety of secondary metabolites that serve as bioactive compounds. Many secondary metabolites are produced in response to environmental signals such as biotic and abiotic stresses. In this study, we identified salt supplementation as one of the stimuli activating secondary metabolism in the model Streptomyces species, Streptomyces coelicolor. Comparative metabolomics revealed overproduction of several known secondary metabolites, most notably undecylprodigiosin and coelimycin P1, in addition to their biosynthetic intermediates and derivatives, as well as many unknown metabolites. Transcriptomic analysis revealed activation of diverse biological processes including cation uptake, compatible solute production, and the phosphate limitation stress response through conserved and species-specific mechanisms, presumably to overcome the increased salinity. This response leads to activation of a variety of regulatory and metabolic pathways required for production of secondary metabolites including activation of conserved metabolic pathways for energy and substrate supply and species-specific secondary metabolite biosynthetic gene clusters. Furthermore, several promoter sequences contributing to upregulation of secondary metabolism induced by salt supplementation were identified. Overall, our data show how S. coelicolor copes with the increased salinity and tailors the cellular metabolism toward secondary metabolism in a conserved and species-specific manner.IMPORTANCEPrecise control of cellular metabolism is critical to ensure directing cellular resources toward metabolic pathways required for the environment. Many Streptomyces species activate production of secondary metabolites upon exposure to environmental stimuli. This study reveals dynamic reprogramming of cellular metabolism in Streptomyces coelicolor under increased salinity, which induces production of various secondary metabolites. Notably, this model biological system redirects cellular resources toward various metabolic pathways required for proper activation of secondary metabolite biosynthesis, including precursor and energy supply and posttranslational modification of biosynthetic enzymes. Interestingly, some pathways are activated by phosphate limitation stress, presumably caused as a result of increased salinity. Certain aspects of this metabolic reprogramming are likely common in many Streptomyces species and may be controlled by rather complex regulatory pathways. Overall, this study unveils how Streptomyces species tailor the cellular metabolism toward secondary metabolism and paves the way for understanding metabolic regulation.

Aluminum (Al³⁺) toxicity is a major limitation to plant productivity in acidic soils, disrupting cellular homeostasis, redox balance, and nutrient uptake. Brassinosteroids are key regulators of plant stress signaling, yet their role in Al³⁺ tolerance remains insufficiently understood. Here, we investigated the signaling functions of 24-epibrassinolide (24-EBL) in mediating aluminum stress responses in Nicotiana tabacum grown under soilless culture conditions. Exogenous 24-EBL significantly alleviated Al³⁺-induced photosynthetic inhibition, as reflected by increased transpiration rate (Tr), stomatal conductance (Gs), net photosynthetic rate (Pn), electron transport rate (ETR), and effective quantum yield of PSII (ΦPSII). Enhanced non-photochemical quenching (NPQ) indicated improved dissipation of excess excitation energy, suggesting photoprotective regulation. At the molecular level, 24-EBL treatment upregulated the antioxidant defense genes CAT1, NtPOD1, and NtSOD3, leading to increased enzymatic activities and reduced reactive oxygen species (ROS) accumulation, thereby preserving membrane stability. Notably, 24-EBL modulated metal detoxification pathways by inducing the expression of the phytochelatin-related genes Pr8 and Pr2, along with Al-ATPase transporters associated with vacuolar sequestration. This was accompanied by altered ion homeostasis, where enhanced Ca²⁺ and K⁺ uptake antagonized Al³⁺ accumulation and restricted its translocation to shoots. The marked upregulation of calmodulin (CaM) suggests that Ca²⁺-dependent signaling plays a central role in 24-EBL-mediated aluminum tolerance. Correlation analysis revealed strong associations between CaM expression, photosynthetic efficiency, antioxidant capacity, and metal detoxification markers. Together, these findings indicate that 24-EBL enhances aluminum tolerance in tobacco through a coordinated signaling network involving Ca²⁺-mediated signal transduction, redox regulation, and metal homeostasis. This study highlights brassinosteroid-calcium crosstalk as a key regulatory module in plant adaptation to aluminum stress.

Approximately 30% of epilepsy patients still develop drug resistance after standard antiepileptic treatment. Therefore, there is an urgent need to identify new drug targets to improve seizure control. Previous studies have shown that NCX1 can regulate the intracellular Ca2+ levels in astrocytes and neurons, which are closely associated with epilepsy. MCC-135 has shown potential as an antiseizure medication due to its ability to downregulate NCX and reduce intracellular calcium overload; however, its role and mechanism in epilepsy remain unclear.

Most cancer cells rely on aerobic glycolysis to support uncontrolled proliferation and evade apoptosis and switch to glutamine metabolism to survive under hypoxic conditions. In hepatocellular carcinoma (HCC), the Wnt/β-catenin pathway acts as a critical driver of metabolic reprogramming and stemness, primarily by enhancing aerobic glycolysis and altering the tumour microenvironment. The Wnt/β-catenin pathway induces activation of enzymes required for glucose metabolism and regulates the expression of glutamate transporter and glutamine synthetase. The objective of this study is to examine the mechanism by which riluzole inhibits HCC growth and induces autophagy. The results indicate that riluzole inhibits cell viability and colony formation of HCC cells and cancer stem cells (CSCs) and induces apoptosis, while sparing human normal hepatocytes. Riluzole induces autophagic cell death by inducing Beclin1 and Atg5. Riluzole inhibits β-catenin, Wnt3a, Wnt5a, Axin1, TCF, LEF and GSK3β expression, and TCF/LEF activity in HCC cells. Inhibition of the Wnt-β-catenin/TCF-LEF pathway by riluzole suppresses the expression of Cyclin D1, Axin2, cMyc, MCT1 and DNMT1. Riluzole inhibits the expression of Glut1 and Glut3, PDK1, LDHA and PKM2, glucose uptake and NAD+ levels. Furthermore, riluzole inhibits glutamate release, which reduces the antioxidant glutathione, leading to increased reactive oxygen species (ROS). Riluzole disrupts mitochondrial homeostasis by increasing Bax/Bcl-2 ratio, resulting in a drop of mitochondrial membrane potential. In conclusion, riluzole inhibits HCC growth by regulating glucose and glutamine metabolism and inducing autophagic cell death, thereby highlighting its therapeutic potential for HCC treatment.

Spinocerebellar ataxia type 8 (SCA8) is a member of a group of dominantly inherited, debilitating neurological diseases caused by CAG•CTG expansions for which there are no effective treatments. RAN translation, which was discovered in SCA8, has previously been shown to occur across CAG and CUG expansion transcripts, making treatments for SCA8 potentially relevant to a broad group of diseases, including SCA1, SCA2, SCA3, SCA6, SCA7, SCA12, Huntington's disease, and myotonic dystrophy type 1. In addition, CUG and CAG expansion transcripts have been reported to cause RNA gain-of-function effects. Using SCA8 BAC transgenic mice as a model for CAG•CTG expansion diseases, we now show that metformin improves ambulatory performance using rotarod, DigiGait, and open-field testing. At the molecular level, metformin-treated mice show reduced RAN protein levels and improved splicing, without altering sense or antisense RNA levels. Metformin-treated mice also show decreased neuroinflammation, with reduced astrogliosis and fewer activated microglia. These data provide strong preclinical support for testing metformin in clinical trials for SCA8 and potentially the broader group of CAG•CTG repeat expansion disorders.

Salt stress is a major abiotic factor limiting plant growth and productivity. One of the primary consequences of salinity is the enhanced production of reactive oxygen species (ROS). This study investigates the role of glycolate oxidase (GOX), a key enzyme in photorespiration and a source of ROS, in the salinity response of Arabidopsis thaliana. We used two GOX T-DNA insertion mutants, gox1 and gox2, alongside wild-type (WT) plants, grown hydroponically under control conditions or exposed to 100 mM NaCl for 24 h. Results showed that shoot and root fresh weight did not differ significantly between genotypes and after 24 h of NaCl treatment. In addition, both mutants, particularly gox2, accumulated less Na+ and Cl- in shoots and roots than WT. This result was supported by ion flux analysis in roots. This fact was associated with the upregulation of key ion transporters: NHX1 (Na+compartmentalization), SOS1 (Na+ exclusion), and KUP11 and HAK5 (K+ uptake). Additionally, gox2 showed differential regulation of nitrate/Cl- transporters, with downregulation of NPF2.4, SLAH1, and SLAH3 and upregulation of NPF2.5 and NPF7.2. Furthermore, gox2 exhibited reduced oxidative damage and increased peroxidase activity under salt stress. These findings suggest that GOX2 expression may regulate plant resilience to salinity by improving ion homeostasis and antioxidative responses.

Nanobiotechnology offers sustainable strategies to enhance plant resistance by activating innate immune responses. This study evaluates the effect of chitosan nanoparticles (CNPs) on transcriptional activation of defense-associated genes in Arabidopsis thaliana.

Celastrus paniculatus (CP) is a traditional medicinal plant widely used in Ayurveda and Southeast Asian medicine for enhancing memory and treating cognitive dysfunction. Although CP has been reported to exhibit antioxidant, anti-inflammatory, and neuroprotective effects, its direct impact on activity-dependent synaptic plasticity remains insufficiently characterized. This study is aimed at investigating the effects of CP seed extract on memory performance and synaptic plasticity in a rat model, with a particular focus on AMPA receptor modulation and associated synaptic proteins. Five-week-old male Sprague-Dawley rats were randomly assigned to five groups: control, CP (80 mg/kg), donepezil (1.5 mg/kg), scopolamine (1 mg/kg), and scopolamine followed by CP. Treatments were administered daily for 14 days. Spatial memory performance was assessed using the Morris water maze. Following behavioral testing, hippocampal tissue was collected for immunohistochemical analysis of Arc protein and Western blotting of pSer831-GluA1, Arc, and PSD-95. CP-treated rats exhibited significantly reduced escape latency and increased time in the target quadrant, with outcomes comparable to those of donepezil-treated rats. In scopolamine-pretreated rats, CP administration reversed memory deficits by enhancing platform crossings and reducing escape latency. Molecular analysis revealed that CP significantly upregulated hippocampal expression of pSer831-GluA1, Arc, and PSD-95, indicating enhanced AMPA receptor trafficking and synaptic integrity. CP seed extract enhances spatial memory and synaptic plasticity by modulating critical molecular components of the glutamatergic synapse. These findings suggest that CP may support memory performance in both baseline conditions and in animals with scopolamine-induced deficits.

The link between glutaminolysis and osteoarthritis (OA) has only recently begun to be elucidated. Here, we report the association of obesity- and injury-induced cartilage damage with impaired glutaminolysis in chondrocytes. Defective glutaminolysis triggered the onset and progression of OA, with enhanced catabolism and decreased anabolism. Supplementation of α-ketoglutarate (αKG), a key component in glutaminolysis and an epigenetic factor, effectively protected cartilage against degradation in vivo via a TCA cycle- and HIF-1α-independent manner. Mechanistically, OA pathogenic factors increased H3K27me3 deposition on promoters of key glutaminolysis genes, including Slc1a5 and Gls1, leading to impaired glutaminolysis. Conversely, αKG facilitated Kdm6b-dependent H3K27me3 demethylation of not only glutaminolysis genes to rescue Gln metabolism but also Ube2o to reverse OA. Elevated Ube2o expression led to TRAF6 ubiquitination and subsequent inhibition of NF-κB signaling, thereby reversing the pathological reprogramming of glycolysis and oxidative phosphorylation and protecting against cartilage destruction. Collectively, these results demonstrated that OA pathogenic factors impair glutaminolysis through epigenetic regulation, which further exacerbate OA. Moreover, αKG restores metabolic homeostasis and alleviates OA through H3K27me3 demethylation.

Small cell lung cancer (SCLC) is known for its rapid growth and early metastasis, and SCLC patients are highly susceptible to chemoresistance. Studies have shown that the combination of ferroptosis induction and TRX pathway inhibition can significantly inhibit SCLC tumor growth, but the molecular mechanisms underlying ferroptosis in SCLC are poorly understood. In this study, we explored the regulatory role of the ALDH1L2-related metabolic pathway in SCLC chemoresistance by machine learning. We found that ALDH1L2 expression is a poor prognostic factor for SCLC patients and that high ALDH1L2 expression can negatively regulate the level of cellular lipid peroxidation and inhibit ferroptosis, thereby promoting SCLC chemoresistance. Mechanistically, ALDH1L2 interacts with the TRX2-PRDX3 antioxidant network to reduce the levels of hyperoxidized PRDX3 and oxidized PRDX3 dimers in the plasma membrane under cisplatin-induced stress and decrease cellular susceptibility to ferroptosis, thus promoting SCLC chemoresistance. In addition, we found that thiostrepton, a PRDX3 inhibitor, can synergize with chemotherapy to suppress tumor growth in SCLC, suggesting that thiostrepton might be a promising new tool for overcoming SCLC chemoresistance.

The expression patterns and potential regulatory correlates of CLDN3 in cancers remain insufficiently characterised, necessitating further investigation. We employed R software alongside bioinformatics platforms to analyse the aberrant expression of CLDN3. Experiments in vitro, including proliferation, wound healing, cell cycle progression and apoptosis assays, were conducted to evaluate the role of CLDN3 in CRC. Co-immunoprecipitation (CO-IP) and immunofluorescence analyses were conducted to investigate the interaction between CLDN3 and TRIM28. Western blotting was employed to evaluate the effect of TRIM28 on CLDN3 SUMOylation and protein stability. CLDN3 was found to be overexpressed in several cancers. Genomic alterations and promoter hypomethylation were identified as key contributors to CLDN3 dysregulation. Bioinformatic analysis suggests that CLDN3 is associated with tumour progression and poor prognosis by influencing pathways, it also contributes to immune dysregulation and chemo-resistance mechanisms. Knockdown of CLDN3 in CRC cells decreased proliferation and migration. CLDN3 overexpression was shown to reduce the sensitivity to 5-FU in CRC cells. CO-IP and immunofluorescence confirmed a direct interaction between CLDN3 and TRIM28. Western blot analysis demonstrated that TRIM28 mediates CLDN3 SUMOylation and degradation. CLDN3 influences the growth and chemotherapy resistance of CRC cells, its interaction with TRIM28 makes the TRIM28/CLDN3 axis as a promising therapeutic target for CRC.

Aberrant DNA methylation patterns are increasingly recognized as contributors to a wide range of conditions, including metabolic, oncogenic, and neurodevelopmental disorders. Nutritional factors, such as choline, can shape methylation potential via methyl group donation. The purpose of this narrative review is to synthesize current evidence on the DNA methylation landscapes underlying health and disease paradigms, with a focus on the role of choline as a compelling target for modulating epigenetic states. A comprehensive literature review search was conducted in PubMed to identify relevant studies, with additional articles retrieved from review papers.

Lineage plasticity has emerged as an important mechanism of treatment resistance in prostate cancer, increasingly associated with loss of androgen receptor (AR) signaling, and in many cases induction of stemness phenotypes and neuroendocrine features. However, targeted therapies for this stage of the disease are currently lacking. In this study, we demonstrated the critical role of the epigenetic regulator UHRF1 in the enzalutamide resistance development of prostate cancer. We have shown that UHRF1 is highly expressed in enzalutamide-resistant prostate cancer cells and its expression correlates with the loss of AR-dependent glandular features. Knocking down UHRF1 led to increased AR expression and enhanced the activity of canonical AR signaling pathway in prostate cancer cells. The combination of UHRF1 knockdown with enzalutamide treatment demonstrated synergistic tumor inhibitory effects both in vitro and in vivo. Mechanistically, UHRF1 was found to bind to AR and promote its ubiquitination and degradation. Furthermore, inhibition of UHRF1 restored AR pathway activity and re-sensitized resistant prostate cancer cells to enzalutamide. Therefore, our findings elucidate an intracellular molecular mechanism that promotes prostate cancer lineage plasticity and suggest that UHRF1 may serve as a potential therapeutic target for overcoming resistance to AR-targeted therapies.