Chemotherapy-induced ncRNA-mediated plasticity is an emerging concept in cancer research. To that end, we observed a cisplatin-responsive regulatory program centered on piRNA activation. OSCC cells exposed to cisplatin markedly promoted the piRNA expression, with piR-hsa-30937 showing the most prominent upregulation. Mechanistically, cisplatin disrupts the OCT1-DNMT1 repressive complex that mediates DNA methylation of transcription factor binding sites of piR-hsa-30937, to derepress its expression. Functionally, piR-hsa-30937 targets GAB2 and sensitizes OSCC cells to cisplatin by suppressing proliferation, enhancing apoptosis, and γ-H2AX accumulation. Furthermore, GAB2 overexpression reversed these effects and desensitized OSCC cells to cisplatin by activating NF-κB-mediated JNK suppression. Overall, cisplatin actively remodels the OCT1-DNMT1-piR-hsa-30937 axis regulating piRNA expression, which in turn potentiates cisplatin cytotoxicity by attenuating GAB2-mediated survival signaling in OSCC.

Small cell lung cancer (SCLC) is an aggressive malignancy characterized by limited therapeutic options. In this study, we identified GL-V9 as a potent anti-SCLC agent that induces apoptosis through oxidative stress. GL-V9 significantly reduced SCLC cell viability in a dose-dependent manner and triggered apoptosis both in vitro and in xenograft models. Mechanistically, GL-V9 increased reactive oxygen species (ROS) levels and lipid peroxidation while impairing mitochondrial function, suggesting that its cytotoxic effects are mediated by oxidative stress. Drug-target interaction analyses revealed that GL-V9 directly binds to STEAP3, a key regulator of iron metabolism, and promotes its degradation via the ubiquitin-proteasome pathway. The loss of STEAP3 disrupted iron homeostasis and exacerbated oxidative stress. In contrast, STEAP3 overexpression attenuated ROS accumulation, mitochondrial damage, and apoptosis both in vitro and in vivo. Further investigation demonstrated that STEAP3 degradation decreased the stability of CISD2, a [2Fe-2S] cluster-containing mitochondrial protein essential for redox balance. GL-V9 downregulated CISD2 in a STEAP3-dependent manner, and restoring CISD2 expression significantly rescued cells from GL-V9-induced oxidative stress and apoptosis. Clinically, both STEAP3 and CISD2 are upregulated in SCLC tumors, and their elevated expression correlates with poor patient survival. Co-expression analysis associated these proteins with pathways involved in oxidative stress and mitochondrial dysfunction. Overall, these findings suggest that GL-V9 induces apoptosis in SCLC by targeting STEAP3 for proteasomal degradation, thereby disrupting the STEAP3-CISD2 axis and promoting oxidative stress-driven cell death. This study identifies a previously unrecognized redox regulatory pathway in SCLC and proposes a potential therapeutic strategy centered on selective induction of oxidative stress.

The aberrant modification level of Histone H3 lysine 9 trimethylation (H3K9me3) is a major barrier for somatic cell nuclear transfer (SCNT) embryo development. The removal of H3K9me3 from the embryonic genome via microinjection of KDM4 mRNA can improve the developmental efficiency. However, this strategy is limiting because of its invasive and time-consuming. In the present study, through comparative transcriptomic analysis with in vivo embryos, we found that porcine SCNT embryos exhibit insufficient zygotic genome activation (ZGA) transcription, along with aberrantly elevated expression of the SUV39H2 and SUV39H1. Then we investigated an alternative approach by inhibiting SUV39H2 and SUV39H1 via their specific inhibitor OTS186935 (targeting SUV39H2) and F5446 (targeting SUV39H1). Individual treatment with either inhibitor significantly reduced H3K9me3 levels and improved blastocyst formation rates. Notably, combined treatment with OTS186935 and F5446 synergistically further enhanced developmental outcomes. This combination treatment potently decreased H3K9me3 levels, rescued transcriptional activity during ZGA, and improved gene expression profiles, making them more closely resemble those of in vivo embryos. Consequently, compared to the control group, the combined treatment significantly increased the blastocyst rate (Treatment: 25.49 ± 4.47% vs. Control: 15.15 ± 2.69%, P < 0.001), blastocyst diameter (Treatment: 116.9 ± 4.37 μm vs. Control: 75.4 ± 2.87 μm, P < 0.001), and total cell number (Treatment: 33.00 ± 3.74 vs. Control: 28.75 ± 6.55, P < 0.05). Our findings demonstrate that dual inhibition of SUV39H1 and SUV39H2 effectively corrects aberrant H3K9me3 modification, ameliorates ZGA defects, and provides a simplified and efficient strategy to enhance the developmental competence of porcine SCNT embryos.

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease, driven by hyperglycemia-induced mitochondrial apoptosis in renal tubular epithelial cells. Death-associated protein kinase 1 (DAPK1) is a key mediator of cell death, but its regulation in DKD remains unclear. Here, we investigated the mechanisms underlying DAPK1 upregulation and its role in mitochondrial apoptosis under high glucose (HG) conditions in HK-2 cells and db/db mouse models. In db/db mice, renal DAPK1 protein levels were elevated, while KLHL20 levels were reduced, correlating with glomerular and tubular injury. In HK-2 cells, HG (33 mM, 48 h) significantly increased DAPK1 mRNA and protein levels while prolonging its half-life. Mechanistically, HG transcriptionally suppressed KLHL20, an E3 ubiquitin ligase adaptor that targets DAPK1 for proteasomal degradation. Co-immunoprecipitation confirmed KLHL20-DAPK1 interaction and showed reduced DAPK1 ubiquitination under HG. Overexpression of KLHL20 restored DAPK1 ubiquitination and reduced its protein levels without affecting mRNA, confirming post-translational regulation. Functionally, DAPK1 knockdown attenuated HG-induced mitochondrial apoptosis. KLHL20 overexpression similarly protected against HG-induced apoptosis, but this effect was abrogated by DAPK1 co-overexpression, establishing DAPK1 as a critical downstream effector. These findings reveal a novel KLHL20-DAPK1 axis where HG stabilizes DAPK1 by downregulating KLHL20, promoting mitochondrial apoptosis in renal tubular cells. Targeting this pathway may offer therapeutic strategies for DKD.

Senescence marker protein-30 (SMP-30; regucalcin) plays a crucial role in intracellular calcium homeostasis. This study investigated hepatic SMP-30 expression during non-alcoholic fatty liver disease (NAFLD) progression and evaluated the therapeutic potential of laminarin (LAM), a brown algae-derived polysaccharide, using high-fat diet (HFD)-fed mice and palmitic acid (PA)-treated Huh7 cells. Mice fed an HFD for 20 weeks developed NAFLD, characterized by elevated ALT/AST levels, hepatic steatosis, and significantly reduced SMP-30 expression. However, LAM treatment administered via drinking water (1%) or intraperitoneal injection (50 mg/kg) significantly attenuated lipid accumulation and restored hepatic SMP-30 expression. LAM reversed PA-induced lipid accumulation and SMP-30 downregulation in Huh7 cells. Mechanistically, LAM modulated the expression of SMP-30 and antioxidant proteins associated with activation of AKT/GSK3β/NRF2 signaling pathway, thereby mitigating the adverse effects of PA-induced toxicity. In conclusion, hepatic SMP-30 expression decreases during NAFLD progression, and LAM treatment restores these levels while alleviating lipid accumulation. These findings suggest that LAM may represent a promising therapeutic agent for NAFLD by improving lipid metabolism and reducing oxidative stress through the regulation of SMP-30.

Exogenous Glutathione S-transferase Mu 2 (GSTM2) supplementation has emerged as a promising strategy to counteract aging. However, approaches to enhance endogenous GSTM2 expression remain underexplored. Here, we identify HCY-NBD, an SO2-targeting small molecular that binds GSTM2 and stabilizes GSTM2 protein levels under high-glucose (HG)-induced vascular endothelial senescence. Mechanistically, HCY-NBD promotes sulfenylation at Cys174 of GSTM2 and inhibits its K48-linked ubiquitination at this residue, thereby stabilizing GSTM2 protein. In cellular studies, we observe that HCY-NBD upregulates GSTM2 and inhibits HG-induced senescence and calcification in vascular endothelial cells. Consistent with this, in vivo administration of HCY-NBD in db/db mice increases GSTM2 levels and mitigates senescence and calcification in the thoracic aorta. Collectively, our findings demonstrate that HCY-NBD inhibits HG-induced vascular senescence and calcification by stabilizing GSTM2 protein levels via enhancing Cys174 sulfenylation and suppression of site-specific ubiquitination-mediated degradation. Here, we first develop a new strategy to enhance endogenous GSTM2 and provide a novel therapeutic strategy for the prevention and treatment of vascular aging.

Brown rot, caused primarily by Monilinia fructicola (M. fructicola) in Asia, is a devastating postharvest disease of peaches. This study demonstrates that diethylthiosulfinate (DETS) exhibits potent antifungal activity against M. fructicola. In vitro assays showed almost complete inhibition of M. fructicola growth on potato dextrose agar (PDA) plates supplemented with 100 ppm DETS. Transcriptomic analysis revealed significant dysregulation of genes involved in carbon metabolism, including starch/sucrose, amino sugar/nucleotide sugar, and galactose metabolic pathways. Expression of key genes critical for carbohydrate utilization-such as sucrose phosphate synthase (SPS), β-D-glucosidase (β-GC), cellulase, and invertase (INV)-was significantly downregulated following DETS treatment. Functional assays confirmed dose-dependent reductions in the ability of M. fructicola to utilize glucose, starch, and sucrose as carbon sources. Mechanistic investigations further showed that DETS disrupted spore production and germination, downregulated the gene expression of cellulase-related cell wall-degrading enzymes (endo-1,4-β-glucanases, 1,4-β-D-glucan cellobiohydrolases, β-glucosidase), and inhibited the activity of pectin-degrading enzymes (pectin lyase [PL] and polygalacturonase [PG]). These effects collectively promoted mycelial cell rupture and efflux of intracellular proteins and nucleic acids. Collectively, these alterations impaired spore germination, mycelial integrity, and pathogenicity. In vivo trials on peaches demonstrated that a 50 ppm DETS treatment reduced necrotic lesion area by 42.4 % compared to the control, highlighting its practical efficacy. These findings establish DETS as a promising antifungal agent that targets metabolic and virulence pathways in M. fructicola, offering a sustainable strategy for postharvest disease management in peaches.

Introduction. The increasing resistance and the pathogen's complex multi-drug resistance mechanisms made the selection of effective antimicrobial treatments more challenging for Pseudomonas aeruginosa (P. aeruginosa). The study aimed to explore the effect of Scutellaria baicalensis, Prunella vulgaris and antimicrobial peptide LL-37 on the virulence factors of P. aeruginosa.Hypothesis. Previous studies have shown that extracts from traditional Chinese medicines, Scutellaria baicalensis and Prunella vulgaris, can also enhance the effects of antibiotics and reduce antibiotic resistance in P. aeruginosa. Antimicrobial peptide LL-37 shows the potential as a new-generation candidate for treating multi-drug-resistant bacteria, which has advantages over traditional antibiotics, whilst the combination role between Scutellaria baicalensis, Prunella vulgaris and LL-37 in P. aeruginosa remains unknown.Aim. We explored whether the combined use of Scutellaria baicalensis, Prunella vulgaris and LL-37 can exert antibacterial effects through the quorum sensing (QS) system.Methodology. The minimal inhibitory concentrations of Scutellaria baicalensis, Prunella vulgaris and LL-37 were determined for PAO1 and PA-ΔlasI/rhlI using micro broth dilution. The antibacterial activity of Scutellaria baicalensis combined with LL-37 and Prunella vulgaris combined with LL-37 was also assessed. The growth abilities of PAO1 were analysed after being treated with Scutellaria baicalensis, Prunella vulgaris and LL-37, respectively. Elastase secretion was measured using Congo red-elastic proteinase assays. And the expressions of QS genes (lasI, rhlR) were analysed by real-time PCR.Results. Single or combined treatments of Scutellaria baicalensis and LL-37 and Prunella vulgaris and LL-37 would significantly reduce elastase secretion. There were no significant differences in proliferation between the groups at any timepoint. All treatments downregulated lasI and rhlR gene expressions.Conclusion.Scutellaria baicalensis, Prunella vulgaris and antimicrobial peptide LL-37 all down-regulate the QS system-related genes of P. aeruginosa, inhibiting the secretion of virulence factors and reducing bacterial toxicity.

Prenatal depression is a prevalent mental health disorder that adversely affects maternal well-being and offspring health. Emerging evidence suggests that vitamin C (L-ascorbic acid), a key antioxidant, may influence this process through the regulation of DNA methylation (DNAm)-a critical epigenetic mechanism governing gene expression. This review summarizes current research on the role of vitamin C in modulating DNAm and explores its potential to mitigate the intergenerational impacts of prenatal depression. We analyze findings indicating that vitamin C may alleviate depressive symptoms and improve offspring health outcomes via epigenetic pathways. Furthermore, we highlight existing research gaps and propose future directions for investigation. By elucidating the interplay between vitamin C, epigenetic regulation, and prenatal depression, this article aims to provide novel insights for developing nutritional strategies to enhance maternal mental health and promote offspring well-being.

Ferritin heavy chain 1 (FTH1) is abnormally expressed in various cancers, but its role and mechanism in endometrial cancer (EC) remain unclear. This study aims to explore the clinical significance, biological functions and potential inhibitor of FTH1 in EC. The expression, prognosis and clinical correlation of FTH1 in EC were analyzed using TIMER, GEO, kaplan-meier plotter and UALCAN databases. Virtual screening and molecular docking were conducted for identifying potential inhibitors of FTH1. In vitro experiments were conducted using human EC cells HEC-1A and RL95-2. Cell proliferation, cell cycle and apoptosis were detected by CCK-8 assay and flow cytometry. The level of reactive oxygen species (ROS) was detected by using the DCFH-DA probe. The levels of malondialdehyde (MDA) and glutathione (GSH) were detected using the corresponding test kits. Western blot was used to detect the expression level of FTH1, AKT and p-AKT. FTH1 was highly expressed in EC tissues and was associated with a shorter overall survival time of patients. Functional enrichment analysis revealed that FTH1 was mainly involved in the iron homeostasis and ferroptosis pathways. FTH1 knockdown inhibits the proliferation of EC cells, induces cell cycle arrest at the G0/G1 phase and triggers cell apoptosis. In EC cells with FTH1 knockdown, the levels of ROS and MDA were significantly increased, accompanied by a decrease in GSH levels. Furthermore, morin had a high binding affinity with FTH1, which also inhibited the malignant phenotypes of EC cells. Morin triggered ferroptosis of EC cells by down-regulating FTH1 expression and inhibiting the PI3K/AKT pathway. FTH1 is a potential prognostic biomarker and therapeutic target for EC. Morin induces ferroptosis of EC cells by regulating FTH1-PI3K/AKT axis, providing a new candidate drug and theoretical basis for the treatment of EC.

Despite decades of investigation into bacterial pathogens, the conditions met by intracellular bacteria are still unclear. These conditions can include access to nutrients, such as amino acids, and exposure to toxic compounds, like copper. To investigate the ability of Brucella abortus, a facultative intracellular pathogen responsible for a major zoonosis, to cope with copper, we performed a Tn-seq analysis to identify copper-sensitive mutants. Unexpectedly, we realized that classical copper resistance systems (involving CopA and CueO homologs) do not appear to be robustly needed, while histidine and purine biosynthesis pathways are crucial to cope with copper. We show that hisA, hisB, hisC, and hisD mutants are auxotrophic for histidine and sensitive to copper. This suggests that the reported attenuation of his mutants in macrophages could be based on auxotrophy and/or copper sensitivity. Therefore, we generated suppressor strains with a restored resistance to copper for hisC, but still auxotrophs for histidine. Our data suggest that this suppression is due to the overproduction of a homolog of OppA, a periplasmic oligopeptide-binding protein. Analysis of these suppressors shows that the absence of histidine biosynthesis capacity, and not copper sensitivity, is required for optimal growth of B. abortus in macrophages.IMPORTANCEInvestigating conditions in which intracellular bacteria grow inside host cells is challenging and often involves the characterization of attenuated bacterial mutants obtained by screening. But a single mutant can display two different phenotypes related to intracellular conditions. It was the case for histidine auxotrophs of Brucella abortus, an important zoonotic pathogen. These histidine auxotrophs are attenuated in a macrophage cell line, and they are also sensitive to copper stress. Using a suppressor strain still auxotroph for histidine but with an improved resistance to copper, we show that histidine auxotrophy, and not sensitivity to copper excess, is the main cause of attenuation in the conditions tested here.

To identify the transcriptomic changes induced by dexamethasone (DEX) in trabecular meshwork (TM) and Schlemm's canal endothelial (SCE) cells with RNA sequencing (RNA-seq).

Tea plant (Camellia sinensis (L.) O. Kuntze) is particularly vulnerable to abiotic stresses, with impacts on its growth and the production of bioactive compounds. SMALL AUXIN UP RNA (SAUR) genes, the largest family of early auxin-responsive genes, regulate plant growth and abiotic stress responses. However, their roles in tea plant remain unknown. In this study, we conducted a comprehensive genome-wide analysis of CsSAURs, including phylogenetic relationships, gene structure, chromosomal distribution, duplication events, motif composition, cis-elements, and gene ontology (GO) annotations. Expression profiles were examined using transcriptome data and validated by qRT-PCR. A total of 97 CsSAURs were identified and classified into eight phylogenetic groups, with 90 mapped to 15 chromosomes and seven to contigs. Genes within the same group exhibit conserved gene structures and motif compositions. Segmental duplication predominantly contributes to family expansion. The predominant CsSAUR expression was found in flowers, with their promoters containing auxin-responsive, phytohormone, and stress-related cis-elements. A limited number of CsSAURs exhibit responsiveness to cold, drought, salinity, and methyl jasmonate (MeJA). Notably, CsSAUR10, 16, and 73 exhibited significant upregulation under abiotic stress and auxin treatment. Overall, this study characterizes the SAUR family in tea plant and highlights its potential roles in the regulation of growth and stress responses. The identified auxin and stress-responsive CsSAURs represent potential targets for genetic improvement of tea plants.

Komagataella pastoris is extensively used as a microbial cell factory for the production of recombinant proteins and high-value compounds. However, tightly controlled promoter systems responsive to safe and economical inducers are required for precise metabolic and pathway engineering in this yeast species. Cumate-inducible promoters are an ideal choice due to the safety and low cost of cumate. In this study, we systematically optimised the insertion sites of the CuO operator sequence within the strong promoter PGCW14 to isolate a high-activity variant that we designated as PGCWCuO03. To fine-tune the expression of the repressor protein CymR, we developed a truncated promoter of PGAP, designated as PGAP200. Based on the optimal promoter PGCWCuO03 and the CymR expression unit, we constructed a robust CymR/CuO-mediated cumate-inducible promoter, designated as Pgc, in K. pastoris. Pgc demonstrated outstanding induction properties, resulting in an approximately 11-fold increase in target protein production following induction. Promoter substitution assays validated the effectiveness of Pgc in temporal gene expression control, highlighting the significant potential of this promoter for both basic research and industrial bioprocessing applications in synthetic biology and biotechnology in K. pastoris.

Human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) constitutes the most challenging subtype of BC, characterized by aggressive tumor proliferation, rapid metastatic potential, and a high propensity for developing resistance, which collectively contribute to a poor clinical prognosis. While the introduction of the novel HER2 inhibitor Pyrotinib has significantly improved therapeutic outcomes, its effectiveness as a monotherapy was substantially constrained by the emergence of acquired resistance. Consequently, discovering novel targeted agents to enhance Pyrotinib's therapeutic effectiveness through combination therapy was urgently required. Cluster of differentiation 24 (CD24) has been identified as a novel immune checkpoint that contributes to tumor-associated immune suppression, however, its involvement in resistance to Pyrotinib remains inadequately understood. In this study, we elucidated the role of CD24 in Pyrotinib-resistant HER2+ BC. Our results demonstrated that CD24 expression was elevated in Pyrotinib-resistant HER2+ BC cells. In vitro experiments revealed that silencing CD24 inhibited proliferation, migration, and invasion of HER2+ BC cells while promoting autophagy, whereas overexpression of CD24 produced opposite effects. Furthermore, CD24 knockdown reduced its expression level by promoting the ubiquitination modification of epidermal growth factor receptor (EGFR), and significantly inhibited its downstream AKT/mTOR signaling pathway. By interacting with EGFR and modulating the mTOR pathway, CD24 acted as a critical regulator of autophagic cell death, thereby enhancing the sensitivity of HER2+ BC cells and reversing Pyrotinib resistance.

This study investigated the effects of fluoxetine on noise-induced injuries to the cochlea and auditory nerve, with a focus on its impact on perineuronal nets (PNNs) and gene expression changes in the ventral cochlear nuclei (VCN).

The objectives of this study were to evaluate the effect of diet type on feed intake, animal performance and intake rank in mature, gestating Angus cows (130 ± 13 days pregnant at trial initiation) and to identify differentially expressed genes (DEG) associated with each diet type. Forty-eight gestating commercial Angus cows (708 ± 52 kg of body weight [BW]; 7 ± 0.75 years old) were assigned to one of two diet sequences, concentrate-forage (CF) or forage-concentrate (FC), representing the order in which the two diets were consumed. In the first period, two of the four pens were assigned to the CF sequence and two to the FC sequence. Each pen contained an automatic waterer as well as four GrowSafe® feed intake units (GrowSafe System Ltd., Airdire, Alberta). The forage diet consisted of 100% processed hay (10.0% CP, 1.98 Mcal ME/kg dry matter [DM]) while the concentrate diet consisted of 43.0% hay, 22.0% corn, 24.0% soybean hulls, and 11.0% supplement on a DM basis (11.7% CP, DM basis and 2.43 Mcal ME/kg DM). Following a 14-day adaptation period, feed intake and BW gain were recorded for 56 days. Subsequently, diet type was switched and followed by 14 days of adaptation to the new diet and 48 days of feed intake and BW gain measurement. Intake and performance data from this crossover study were analyzed using mixed model methods in SAS v9.4. There was a diet by period interaction (P < 0.01) for daily gain (ADG) with cows in the FC sequence gaining more weight than expected while consuming forage. Spearman rank correlation for dry matter intake was 0.70 (P < 0.01) for FC cows and 0.36 (P < 0.1) for CF cows. In contrast, there was no significant relationship for ADG among the two diet types, regardless of sequence (P > 0.4). In total, RNA sequencing of muscle tissue from the first period identified DEG associated with diet type. Enriched biological processes were identified by functional enrichment analysis of the DEG using g: Profiler and were primarily associated with energy metabolism and lipid biosynthesis. The results of this study support the hypothesis that gene expression in muscle responds differently when cows consume low-quality forage versus high-quality, energy-rich diets, even though feed intake rank correlations were high in the FC sequence and moderate in the CF sequence.

Biologic therapies targeting TNF-α in inflammatory and autoimmune diseases underscore its central role in pathological inflammation. Epigenetic mechanisms are increasingly recognized as critical modulators of disease-associated gene expression, and advancing epigenetic-based therapeutics requires deeper insight into the transcriptional networks governing inflammatory responses. Here, we investigate the epigenetic regulation of inflammation-induced TNF-α transcription and identify lead compounds that suppress TNF-α expression in human macrophages.

Oral squamous cell carcinoma is the most common oral malignancy and poses a major health challenge because of late-stage diagnosis, high recurrence, and resistance to treatment. In addition to genetic mutations, oral squamous cell carcinoma is strongly influenced by epigenetic alterations, including abnormal DNA methylation, histone modifications, and dysregulated non-coding RNAs. These changes contribute to the inhibition of tumor suppressor genes and regulation of oncogenic pathways, which promote cancer progression. Oxidative stress and excessive reactive oxygen species further drive these epigenetic changes, creating a vicious cycle that fuels carcinogenesis. Natural antioxidants, including genistein, epigallocatechin gallate, resveratrol, lycopene, and quercetin, have shown promise in preventing and treating oral squamous cell carcinoma. Their multi-targeted actions involve the inhibition of DNA methyltransferases, reversal of tumor suppressor gene promoter hypermethylation, regulation of histone acetylation and methylation, and regulation of microRNAs (miRNAs) that suppress oncogene activity. These compounds restore normal gene function with low toxicity to healthy cells, making them appealing candidates for personalized therapy. By targeting both oxidative stress and epigenetic instability, natural antioxidants offer a promising strategy against the core mechanisms of oral squamous cell carcinoma. Understanding this molecular interplay may employ more effective prevention and therapeutic approaches in future oral squamous cell carcinoma management paradigms.

Inflammatory arthritis is a term used to describe a diverse group of rheumatic disorders involving the inflammation and hyperproliferation of synovial joints and systemic manifestations. Oleacein (OLA) is one of the most abundant secoiridoids in extra virgin olive oil, the principal source of fat in the Mediterranean diet, which has been shown to exhibit beneficial effects. The objective of the study was to explore the antioxidant and anti-inflammatory effects induced by OLA in a human cell line of synovial cells (SW982), as well as to evaluate its possible role as an epigenetic modulator through the regulation of DNA methylation. Sulforhodamine B assay was utilised to assess cell viability. The levels of inflammatory marker production (MMP-1, MMP-3, TNF-α, IL-1β, IL-6, and PGE2) were evaluated by ELISA, and IL-8 gene expression was analysed by RT-qPCR. The expression of pro-inflammatory enzymes, including COX-2 and mPGES-1, and signaling pathways (MAPK, NF-κB, Keap1/Nrf-2/HO-1 and inflammasome) were evaluated by western blotting. In addition, global DNA methylation was analysed by ELISA, and we studied the gene expression of DNMT1/3A enzymes by RT-qPCR. OLA exhibited anti-inflammatory and antioxidant effects through the regulation of key inflammatory signaling pathways such as inflammasome, MAPK, NF-κB, and the Keap1/Nrf-2/HO-1 axis. In addition, it reduced the production and expression of pro-inflammatory markers (COX-2, mPGES-1, MMP-1, MMP-3, IL-8, IL-6, TNF-α and PGE2) and regulated IL-1β-induced changes in DNA methylation modulating DNMT1 and DNMT3 gene expression and global DNA methylation. These results show OLA as a promising epigenetic regulator of the inflammatory response in rheumatic diseases.