Search Results (413)

Background: Prostate cancer (PCa) is the leading male urinary malignancy globally. Our previous article demonstrated the anti-PCa activity of Euphorbia humifusa Willd water extract (EHW) and some of its compounds via downregulating AR expression, but the anti-PCa active compounds from Euphorbia humifusa Willd (EH) and their mechanisms of action are yet to be clarified. Thus, the current article studied the in vitro anti-PCa effects of 3,3′-di-O-methylellagic acid (3,3′-di-O-Me-EA) derived from EHW and the related mechanism involved. Methods: 3,3’-di-O-Me-EA was isolated from EHW applying bioassay-guided fractionation. The spectroscopic methods were used to determining the structure of 3,3′-di-O-Me-EA. The drug-likeness and ADMET properties (absorption, distribution, metabolism, excretion, and toxicity) of 3,3′-di-O-Me-EA were analyzed in silico. Molecular docking and real-time surface plasmon resonance (SPR) analysis were performed to measure the interaction of 3,3′-di-O-Me-EA and VDAC1 protein. The viability and apoptosis of 22RV-1 and DU145 PCa cells were determined using MTT and Annexin V-FITC staining assay, respectively. q-PCR and Western blot experiments were used to analyzing the gene and protein expressions of VDAC1. Results: 3,3′-di-O-Me-EA was isolated and purified from EHW with a purity of ≥90.06%, and its structure was identified by HRTOF mass, NMR, and an authentic standard. In silico ADMET analysis indicated its favorable drug-like and pharmacokinetic properties. Molecular docking and SPR results confirmed that 3,3′-di-O-Me-EA could bind with the VDAC1 protein. Moreover, 3,3′-di-O-Me-EA dose- and time-dependently inhibited 22RV-1 and DU145 PCa cell viability, and induced apoptosis in a dose-dependent manner (p < 0.05). RT-qPCR and Western blot results showed that 3,3′-di-O-Me-EA dose-dependently up-regulated VDAC1 gene and protein expression levels in 22RV-1 and DU145 cells (p < 0.05). Meanwhile, in VDAC1-depleted 22RV-1 and DU145 cells, 3,3′-di-O-Me-EA down-regulated VDAC1 gene and protein expression levels, increased cell viability, and inhibited apoptosis compared to 22RV-1 and DU145 cells (p < 0.05). Furthermore, 3,3′-di-O-Me-EA enhanced VDAC1 gene and protein expression levels, inhibited cell viability, and induced apoptosis in VDAC1-overexpressed 22RV-1 and DU145 cells compared with 22RV-1 and DU145 cells (p < 0.05). Overall, EH active compound 3,3′-di-O-Me-EA may inhibit viability and induce apoptosis of 22RV-1 and DU145 PCa cells via up-regulating VDAC1 gene and protein expression levels. Conclusion: The results indicated that the 22RV1 and DU145 PCa cell viability inhibitory effects of 3,3′-di-O-Me-EA isolated from EH may be mediated by induction of apoptosis through up-regulation of VDAC1 gene and protein expression levels. Full article

Background/Objectives: Apples are nutritionally valued for their dietary fibre and polyphenols, which influence gut microbial metabolism. However, the metabolic consequences of short-term apple consumption on the human gut environment have not yet been thoroughly investigated. This study aimed to investigate the impact of short-term supplementation of the habitual diet with Gala apples on the human faecal metabolomic profile and to identify metabolite changes reflecting microbial fermentation processes. Methods: A pilot dietary intervention was conducted in 15 healthy adults (6 females, 9 males; age 18−30 years). Participants consumed three Gala apples per day as part of their habitual diet for three consecutive days, one with each main meal. Faecal samples were collected before and after the intervention. Metabolic profiling was performed using ¹H NMR spectroscopy. Results: Multivariate analysis showed no clear clustering between pre- and post-intervention samples, suggesting that inter-individual variability exceeded the overall intervention effect. Univariate analysis showed a nominal increase in faecal methanol levels post-intervention (β = +0.72, FC ≈ 2.05, p = 0.012); however, this change did not remain statistically significant after correction for multiple testing (q = 0.27). Several other metabolites showed nominal decreases following the intervention, including amino acids, branched-chain fatty acids, short-chain fatty acids, and aromatic microbial metabolites. Conclusions: Short-term Gala apple consumption was associated with nominal, metabolite-specific changes in the faecal metabolome without clear global shifts. These findings may show immediate metabolic responses to increased intake of apple-derived substrates; however, given the exploratory design, small sample size, and high inter-individual variability, causal relationships cannot be established. Further studies in larger, controlled cohorts incorporating complementary approaches are required for confirmation. Full article

Fly ash is an effective supplementary cementitious material for reducing clinker consumption and carbon emissions, but its low early reactivity often results in delayed hydration and insufficient early-age strength. This study investigated the age-dependent role of graphene oxide (GO) in fly ash-blended cementitious materials by combining compressive strength testing with X-ray diffraction (XRD), thermogravimetric analysis (TG-DTG), ²⁹Si magic-angle spinning nuclear magnetic resonance (²⁹Si MAS NMR), and scanning electron microscopy coupled with energy-dispersive spectroscopy (SEM-EDS). Fly ash replacement levels of 10%, 20%, and 30% were considered, and 0.07% GO was introduced to evaluate its effect at 3, 7, and 28 days. The results showed that fly ash reduced the 3-day compressive strength, whereas the strength differences became much smaller at 28 days. GO enhanced the compressive strength of all fly ash-blended mixtures. XRD and TG-DTG results showed that GO refined Ca(OH)₂ crystallization and reduced the retained CH content, indicating more effective CH utilization during hydration and pozzolanic reaction. At 28 days, the incorporation of 0.07% GO increased the compressive strength of the 30% fly ash mixture from 47.38 MPa to 56.58 MPa, while reducing the total CH content from 14.20% to 12.89%, indicating enhanced CH utilization and gel development. ²⁹Si MAS NMR further demonstrated that GO promoted a more mature and polymerized silicate gel structure, as evidenced by lower Q⁰ fractions, higher mean chain length, and higher proportions of more polymerized silicate species. SEM-EDS observations confirmed that GO led to a denser matrix, less dominant coarse CH, and lower Ca/Si and Ca/(Si + Al) ratios. Overall, GO improved the mechanical performance of fly ash-blended cementitious materials through coupled regulation of hydration products, silicate gel polymerization, and matrix densification. Full article

Background: Guanine-rich DNA regions can fold into G-quadruplex (G4) structures, which are prevalent in telomeres and oncogene promoters, making them attractive targets for anticancer therapeutics. Small molecules capable of selectively stabilizing G4 DNA can disrupt telomerase activity and oncogene expression, offering a promising strategy for cancer intervention. Methods: A rationally designed series of DPPZ–anhydride-conjugated ligands (1 and 2) and their corresponding quaternized derivatives (1-q and 2-q) were synthesized to investigate the combined effects of π-extension, bromine substitution, and cationic modification on DNA recognition. The synthetic strategy relied on the incorporation of a highly planar DPPZ–anhydride scaffold to enhance π-surface area, followed by selective quaternization to introduce permanent positive charge and reinforce electrostatic interactions with the DNA backbone. All compounds were fully characterized by NMR and spectroscopic methods. The DNA-binding properties of the ligands were systematically evaluated toward duplex (ds-DNA) and G-quadruplex (G4-DNA) structures using UV–Vis absorption titration, fluorescence intercalator displacement (FID) assays, and competitive dialysis experiments. Quaternization markedly enhanced intrinsic binding constants and significantly reduced DC₅₀ values, particularly for G4-DNA. While bromine substitution increased overall binding affinity, it did not substantially improve topology selectivity. Among the series, compound 1-q exhibited the most favorable balance between affinity and G4 selectivity. Results: The interaction of the compounds with BSA was quantified using Stern–Volmer quenching constants, which demonstrated a clear trend of enhanced quenching efficiency upon modification. The binding strength followed a descending order of 1-q > 2-q > 1 > 2, highlighting the superior performance of the first series over the second. These findings indicate that the structural features of 1-q facilitate a more robust interaction within the hydrophobic pockets of the protein. Conclusions: Overall, the results demonstrate that strategic π-conjugation combined with electrostatic reinforcement provides an effective approach for the development of topology-selective DNA-binding ligands. Full article

Ethnopharmacological relevance. Withania somnifera (L.) Dunal, widely used in traditional medical systems such as Ayurveda, Unani, and Middle Eastern folk medicine, is valued for its adaptogenic, anti-inflammatory, neuroprotective, antimicrobial, and anticancer properties. These activities are primarily attributed to withanolides, with Withaferin A recognized as one of the most bioactive constituents. Although traditional preparations often rely on the root, leaf use provides a more sustainable alternative and may yield significant quantities of active metabolites. Identifying efficient, modern extraction technologies that can enhance the recovery of bioactive compounds from leaves is essential for developing effective, standardized ethnopharmacological formulations. Materials and methods. Plants of W. somnifera grown from seeds were subjected to different environmental conditions (control, drought, cold, yeast extract treatment). Leaves were extracted using Pressurized Cyclic Solid–Liquid Extraction (PCSLE) with hydroalcoholic solvents and compared with conventional infusion of dried leaves. Extracts were fractionated with solvents of varying polarity and analyzed by TLC, HPLC, and NMR for quantification of Withaferin A. Expression levels of key withanolide-biosynthetic genes (CAS, SMT1, DWARF1, CYP71, CYP76) were assessed using qRT-PCR. Antimicrobial activity of pure Withaferin A, aqueous extract, and hydroalcoholic PCSLE extract was evaluated through MIC and MBC assays against Gram-positive and Gram-negative strains. Cytotoxic activity was measured via MTT assays in six human cancer cell lines after 3, 6, and 24 h of treatment. Results. PCSLE yielded substantially higher levels of Withaferin A than traditional infusion, especially in medium-polarity fractions (chloroform and ethyl acetate), with concentrations reaching 0.70% in fresh leaf mass (4.8% dry weight), compared to 0.11% obtained by infusion. Gene expression analysis revealed that 24-week-old plants exhibited the highest transcription of withanolide-biosynthetic genes, and drought stress significantly upregulated CAS, SMT1, DWARF1, CYP71, and CYP716, indicating enhanced metabolic flux toward withanolide production. Hydroalcoholic PCSLE extracts showed broad-spectrum antimicrobial activity, with MIC and MBC values comparable to pure Withaferin A and demonstrating bactericidal effects against Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, and Listeria monocytogenes. The aqueous extract showed activity only against Gram-positive strains. Cytotoxicity assays demonstrated an optimistic, dose-dependent reduction in cell viability across all tumour cell lines treated with the hydroalcoholic PCSLE extract, closely mirroring the activity of pure Withaferin A and consistently exceeding the effect of the aqueous extract. IC50 values confirmed the high bioactive content of PCSLE extracts and suggested mechanisms like those known for Withaferin A. Conclusions. PCSLE proved to be a highly efficient extraction technology for obtaining leaf extracts rich in Withaferin A, outperforming conventional extraction methods while exploiting sustainable plant tissue. Developmental stage and drought stress significantly modulated the expression of genes involved in withanolide biosynthesis, highlighting agronomic strategies capable of enhancing metabolite production. Hydroalcoholic PCSLE extracts exhibited antimicrobial and cytotoxic activities comparable to pure Withaferin A, supporting their relevance as promising therapeutic candidates. These findings advocate for the use of W. somnifera leaves as a sustainable source of bioactive compounds and demonstrate that advanced extraction technologies can contribute to the development of innovative ethnopharmacological preparations for antimicrobial and anticancer applications. Full article

In order to find green fungicides derived from natural products, 22 unreported anethole-based thiazolinone-hydrazone compounds were designed and synthesized, and their structures were characterized by FT-IR, ¹H NMR, ¹³C NMR, and HRMS. At a concentration of 50 mg/L, the preliminary antifungal activity of the target compounds against eight plant pathogens was evaluated. The results showed that 5q (R = m-OH C₆H₄) exhibited the best inhibitory activity against most of the tested plant pathogenic fungi, demonstrating that this compound had certain broad-spectrum antifungal activity. In addition, a reasonable and effective 3D-QSAR model (r² = 0.994, q² = 0.529) was established using the comparative molecular field analysis (CoMFA) method to study the relationship between the structures of the target compounds and their antifungal activity against Physalospora piricola. Meanwhile, the results of electrostatic potential calculation of the compounds indicated that the electronic effect caused by different substituents on the benzene ring might be one of the factors affecting antifungal activity. In addition, frontier molecular orbital calculations implied that the anethole moiety and the thiazolinone-hydrazone-benzene structure in the target compounds might play an important role in antifungal activity. The potential binding mode between the target compound 5q (R = m-OH C₆H₄) and the homology-modeled succinic dehydrogenase was explored by molecular docking. Full article

(1) Background: Gastric cancer (GC) remains a major global health challenge due to its high heterogeneity and aggressive progression. The discovery of novel bioactive molecules with anticancer properties has, therefore, become a critical research focus. In this study, we synthesized and characterized 4,4′-(5,8-dioxa-2,11-diazadodecane-1,11-diene-1,12-diyl)diphenol (DODP) and evaluated its anticancer potential using molecular docking, bioinformatics, and experimental analyses. (2) Methods: The chemical structure of DODP was confirmed through ¹H and ¹³C NMR spectroscopy. Molecular docking was conducted to examine the interaction of DODP with apoptosis and cell cycle-related proteins (TP53, MDM2, and MYC) and the immune checkpoint marker CD274 (PD-L1). Cytotoxicity against AGS GC cells was determined using the MTT assay at concentrations ranging from 0.01 to 50 µM, and gene expression alterations were analyzed by quantitative polymerase chain reaction (qPCR) and bioinformatics evaluation. (3) Results: NMR data verified the successful synthesis of DODP. The docking results indicated strong binding affinity, especially with TP53 and CD274. DODP showed notable cytotoxicity after 72 h of exposure and induced upregulation of TP53, MYC, and CD274 and downregulation of MDM2 in AGS cells. Although the patterns were consistent with cell-based and bioinformatic analyses, significant discriminatory ability in blood samples was observed only for MYC (AUC = 0.651; p = 0.044). (4) Conclusions: DODP influenced apoptosis-associated transcriptional responses in GC, offering early mechanistic evidence that should be evaluated in more comprehensive biological models. Full article

Agro-industrial byproducts from Colombian Passiflora species represent an underexplored source of chemically diverse metabolites with promising cosmetic and pharmaceutical potential. This study investigated the chemical profiles and photoprotective potential of polar extracts obtained from byproducts (leaves, pericarps, and seeds) of six commercially relevant Passiflora species cultivated in Colombia (P. ligularis, P. edulis var. edulis, P. edulis var. flavicarpa, P. maliformis, P. quadrangularis and P. tarminiana × P. tripartita). Butanolic fractions from leaves and pericarps and hydroethanolic seed extracts were analyzed using ¹H NMR, GC-FID, GC-MS and UHPLC-qTOF. NMR profiling revealed aromatic signals mainly associated with flavonoids and stilbenoids in leaves and pericarps, while seeds exhibited abundant fatty acids, particularly linoleic acid. Molecular networking enabled the visualization of chemical diversity and supported the identification of 74 metabolites, including flavonoids, saponins, and stilbenoids, using Global Natural Products Social Molecular Networking (GNPS), SIRIUS (Version 6.0.5) software, and comparison with the literature. In vitro spectrophotometric photoprotective evaluation using the Mansur equation at 200 ppm showed that leaf extracts exhibited the highest sun protection factor (SPF) values, followed by seeds and pericarps, consistent with their phenolic composition. All active extracts demonstrated broad-spectrum protection, with high UVA ratios and critical wavelength values. These findings highlight the potential of Passiflora byproducts as sustainable sources of natural photoprotective agents for cosmetic applications. Full article

Diabetic cognitive impairment (DCI) is a serious and growing public health concern. The role of N6-methyladenosine (m⁶A), the predominant mRNA modification in the mammalian brain, in DCI pathogenesis remains not fully elucidated. Here, GEO-derived diabetes datasets were combined with in vivo and in vitro models to reveal aberrant expression of m⁶A-related genes. The results showed that the overall level of m⁶A RNA methylation in both the diabetic group and the high-glucose group was significantly decreased compared to the normal group. In addition, the expression of methyltransferase METTL3, which is involved in the regulation of m⁶A RNA methylation, was downregulated in both diabetic and hyperglycemic groups, and was positively correlated with the downregulation of the overall m⁶A level. Neuronal models with stable METTL3 knockdown were generated using lentiviral transduction. Subsequent ¹H-NMR metabolomic and MeRIP-qPCR analyses demonstrated that METTL3 deficiency disrupts key metabolic pathways, including phosphatidylethanolamine and phosphatidylcholine biosynthesis and glucose–alanine metabolism, and identified Fgf15 (the mouse ortholog of human FGF19) and H6PD as candidate downstream targets. Collectively, these data suggest that METTL3-dependent m⁶A RNA methylation alterations may contribute to DCI through metabolic dysregulation, positioning METTL3 as a promising therapeutic target for DCI. Full article

Background/Objectives: This pilot study aimed to evaluate the metabolic profiles in plasma and cerebrospinal fluid (CSF) of 14 patients with acute lymphoblastic leukemia (ALL) and plasma of a control group, using proton magnetic resonance spectroscopy (¹H NMR). Methods: Multivariate analysis, including orthogonal partial least-squares discriminant analysis (OPLS-DA), was used to analyze the metabolome composition. Results: Significant differences in plasma metabolic profiles were found between the ALL and control groups. We detected elevated levels of formate, citrate, and glycerophosphocholine (GPC), along with decreased concentrations of glutamine and myo-inositol. The OPLS-DA model showed stability, with R²Y = 69.7% and Q² = 45.15%. Additionally, we observed differences in chemical shifts for leucine, myo-inositol, alanine, phenylalanine, and valine between CSF and plasma in patients with ALL. Conclusions: Our findings suggest that metabolomic analysis with ¹H NMR is a promising tool for identifying potential molecular biomarkers and for deepening our understanding of metabolic reprogramming in pediatric ALL. The observed metabolic differences highlight the potential involvement of the central nervous system in the disease’s pathophysiology. Full article

Background/Objectives: Vitamin B12 deficiency affects up to 40% of certain populations worldwide and has been associated with cardiometabolic risk. However, its relationship with detailed lipoprotein subfractions remains poorly defined. This study aimed to investigate the association between serum vitamin B12 levels and atherogenic lipid profiles using NMR-based lipoprotein subfraction analysis. Methods: In this retrospective cross-sectional study, data from 20,665 apparently healthy adults undergoing routine health screening were analyzed. Participants were categorized into quartiles based on serum vitamin B12 levels (Q1: ≤328 pg/mL; Q4: ≥540 pg/mL). Lipoprotein subfractions were quantified using Bruker NMR spectroscopy. The Atherogenic Index of Plasma was calculated as log₁₀(triglycerides/HDL-cholesterol). Statistical analyses included ANCOVA adjusted for age, with corrections for multiple comparisons. Results: Higher serum B12 levels were significantly associated with a more favorable lipid profile. Specifically, AIP values decreased progressively across B12 quartiles (Q1: −0.051 ± 0.273; Q4: −0.170 ± 0.294; p < 0.001, partial η² = 0.017). HDL-cholesterol increased (p < 0.001, partial η² = 0.008), while triglycerides and VLDL-TG subfractions (VLDL1-TG: p < 0.001; VLDL5-TG: p = 0.029) declined with higher B12 levels. Among LDL subfractions, small dense LDL (LDL5-TG) exhibited a consistent inverse association with B12 (p = 0.002, partial η² = 0.001). These associations were robust across all age strata, with no significant interaction between B12 levels and age. Conclusions: Serum vitamin B12 levels are inversely associated with atherogenic lipid parameters in a large cohort of asymptomatic individuals. Higher B12 status correlates with lower AIP, reduced triglyceride-rich lipoproteins, and diminished small dense LDL particles across all age groups. These findings suggest that B12 status may serve as a potential biomarker in cardiovascular risk assessment and highlight the need for prospective interventional studies. Full article

Epigenetic and stress-response pathways play central roles in cancer progression and represent attractive therapeutic targets. In this study, a series of dipyridothiazine–1,2,3-triazole hybrids bearing p-fluorophenyl and p-trifluoromethylphenyl substituents was synthesized via efficient dipolar cycloaddition reactions. Structural characterization was performed using ¹H, ¹³C, and ¹⁹F NMR spectroscopy and high-resolution mass spectrometry. Anticancer activity was evaluated using WST-1 and MTT assays against human cancer cell lines SNB-19 (glioblastoma), C32 (amelanotic melanoma), A549 (lung carcinoma), and MDA-MB-231 and MCF-7 (breast cancer), as well as normal HFF-1 fibroblasts and HaCaT keratinocytes, with doxorubicin and cisplatin as reference drugs. The hybrids TDT2b and TDT3b containing a p-trifluoromethylphenyl moiety showed the highest cytotoxicity and cancer cell selectivity. RT-qPCR analysis of H3, TP53, CDKN1A, BCL-2, and BAX expression for the lead compound TDT2b revealed modulation of chromatin organization, p53-dependent stress responses, apoptosis, and cell cycle regulation. Molecular docking studies with human histone deacetylase 6 (HDAC6) demonstrated favorable binding of TDT2b and TDT3b, supporting their role as potential epigenetic anticancer agents. Full article

Terpinen-4-ol (TP4O) is a key monoterpene alcohol commonly used as a quality and authenticity marker in essential oils, cosmetics, herbal products, and pharmaceutical formulations. However, reliable and comparable quantification of TP4O across laboratories is challenged by variability in natural matrices and the limited availability of well-characterized, traceable reference materials. In this study, a high-purity certified reference material (CRM) of TP4O was developed and characterized by the National Institute of Metrology (Thailand). The material’s purity was determined using two independent and complementary approaches: a mass balance method (MB) method based on gas chromatography with flame ionization detection (GC-FID), Karl Fischer coulometric titration (KFT), and thermogravimetric analysis (TGA), and a quantitative ¹H NMR (qNMR) method employing DSS-d₆ as an internal standard. The purity values obtained using the MB (98.41 ± 0.09%) and qNMR (99.13 ± 0.94%) methods were statistically equivalent (p > 0.05). Based on the combined evaluation, a certified purity value of 98.77% with an expanded uncertainty of 3.05% (k = 2) was assigned. Homogeneity and short- and long-term stability assessments confirmed the suitability of the material for its intended use. This TP4O CRM provides an SI-traceable, high-purity reference to support calibration, method validation, and quality assurance in analytical applications involving essential oil components. Full article

Background: Fructans are fructose-based polysaccharides with diverse biological activities; however, their direct activity on skin cells remains unresolved. This study investigated the biological activity of fructan extracted from rakkyo (Allium chinense) (RF) and examined its effects on extracellular matrix (ECM) metabolism, particularly collagen and hyaluronan synthesis, in human dermal fibroblasts. Methods: RF was prepared from fresh rakkyo bulbs by aqueous extraction, alkaline clarification, and membrane filtration. The average molecular weight and structural characteristics of RF were analyzed using size-exclusion chromatography and ¹³C NMR spectroscopy. Normal human dermal fibroblasts (NHDFs) were treated with RF by culturing cells in RF-supplemented medium (0.1–1.0 mg/mL). Cell viability and viable cell number were evaluated using the thiazolyl blue tetrazolium bromide and trypan blue exclusion assays, respectively. Expression of ECM-related genes was analyzed by qRT-PCR, and collagen and hyaluronan production were quantified by Sirius Red staining and ELISA. Results: RF had an average molecular weight of approximately 11,500 Da and consisted of nearly equal proportions of inulin- and levan-type fructans. RF (≤1 mg/mL) increased the number of viable cells and markedly upregulated collagen, type I, alpha 1 (COL1A1) and hyaluronic acid synthase 2 (HAS2) expression while downregulating Hyal1 expression. After 9 days of treatment, the cumulative production of type I collagen and hyaluronic acid increased by 3.8- and 1.3-fold, respectively, as compared with controls. Upregulation of lysyl oxidase (LOX) mRNA suggested enhanced collagen cross-linking, whereas MMP-1 showed only modest induction. Conclusions: Rakkyo-derived fructan directly stimulates collagen and hyaluronan synthesis in dermal fibroblasts, likely through regulation of ECM-related genes. These results suggest that rakkyo-derived fructan modulates ECM-related readouts in NHDFs under controlled in vitro conditions. Further validation in more complex skin models and in vivo studies is necessary. Full article

Background/Objectives: Cardiovascular involvement drives morbidity and mortality in systemic lupus erythematosus (SLE). Echocardiography has limited predictive value for long-term outcomes, and subclinical right ventricular (RV) remodeling is poorly characterized. Metabolic dysregulation may influence immune activation and myocardial injury. This study investigates whether baseline metabolomic profiles are associated with longitudinal RV changes and disease progression in SLE. Methods: In this prospective, single-center study, patients with established SLE and no known cardiac disease underwent baseline clinical assessment, plasma metabolomic profiling, and advanced echocardiography, including 3D RV analysis. Echocardiography was repeated after 6 years. Metabolomics was performed using NMR spectroscopy and GC–MS. Disease progression was assessed via the SLICC/ACR damage index (SDI), defining clinical stability as ΔSDI = 0 and worsening as ΔSDI ≥ 1. Results: Twenty-five patients completed the follow-up (88% female; mean age 51 ± 13 years). Despite normal echocardiographic values, subtle but significant RV changes were observed, remaining within reference ranges, including mild declines in fractional area change and septal longitudinal strain (p < 0.05). Clinically worsened patients showed reduced TAPSE, while stable patients had slight increases (p < 0.05). Multivariate metabolomic analysis distinguished stable from worsened patients (R²Y = 0.772; Q² = 0.483), primarily driven by higher 2-aminoheptanedioic acid values in those with progression (p < 0.05), along with trends toward higher fumarate and lower fructose and glucopyranose. Conclusions: Baseline metabolomic and advanced echocardiographic profiling may identify SLE patients at risk of disease progression. Longitudinal echocardiography enables monitoring of subtle RV changes, supporting personalized surveillance to detect early subclinical trajectories before overt dysfunction develops. Full article