Search Results (765)

Alcohol consumption is associated with increased breast cancer risk, partly due to the accumulation of toxic aldehydes like acetaldehyde, a carcinogenic byproduct of ethanol metabolism. Acetaldehyde Dehydrogenase 2 (ALDH2), a key mitochondrial enzyme, detoxifies acetaldehyde and other reactive aldehydes that drive oxidative stress, DNA damage, and hormonal dysregulation—processes central to carcinogenesis. Although alcohol consumption has been implicated in breast cancer, the role of ALDH2 deficiency itself, in the absence of exogenous alcohol exposure, in mammary gland biology and cancer susceptibility remains unclear. Genetic variants that impair ALDH2 activity are highly prevalent in East Asian populations, where carriers of inactive ALDH2 alleles exhibit impaired aldehyde detoxification. While such individuals are more susceptible to alcohol-related cancers, the effects of ALDH2 deficiency on mammary gland development and homeostasis without alcohol exposure remain unexplored. To investigate the effects of ALDH2 deficiency on mammary proliferation and development, we utilized a C57BL/6-based ALDH2 knockout (Aldh2−/−) mouse model. Our findings revealed that Aldh2−/− mice displayed hyperproliferative mammary glands with increased epithelial cell density, ductal expansion, and increased numbers of Ki67+ cells. Flow cytometry analysis revealed expansion of luminal and basal epithelial subpopulations, accompanied by enhanced mammary epithelial stemness, as indicated by increased mammosphere formation and colony-forming efficiency. At the molecular level, ALDH2 deficiency activated oxidative stress pathways, reflected by elevated 8-OHdG, p38 MAPK, NF-κB, and Nrf2 signaling, along with DNA damage responses involving p53 and H2A.X. We also identified a novel upregulation of RANK and RANKL in Aldh2−/− mammary glands, identifying the RANK/RANKL upregulation associated with NF-κB/p38 MAPK activation and enhanced mammary stemness. Furthermore, hormonal dysregulation was observed, with a significant increase in ERα and PR expression and phosphorylation. Dysregulated ER signaling correlated with enhanced erbB3 activation and downstream signaling, including the cyclin D1–pRb-E2F1 axis. These findings suggest that ALDH2 deficiency, possibly through accumulated endogenous aldehydes, profoundly alters mammary morphogenesis, epithelial repopulation, and stemness. These effects are associated with activation of oxidative stress and DNA damage pathways, together with upregulation of RANKL, estrogen receptor and receptor tyrosine kinase signaling. This study is the first to identify ALDH2 deficiency as a novel factor associated with mammary epithelial alterations that may create a tissue state that could predispose to oncogenic transformation. Full article

Conjunctival lymphoma classically appears as a painless salmon-pink subepithelial infiltrate, but its indolent forms can closely imitate inflammatory ocular surface disease and delay diagnosis, particularly when an uncommon subtype such as small lymphocytic lymphoma presents bilaterally and in isolation. A woman in her early fifties presented with one month of left ocular discomfort and sectoral redness, and slit-lamp examination revealed two multilobulated hyperaemic bulbar conjunctival nodules, clinically indistinguishable from nodular episcleritis. Topical corticosteroids and a topical non-steroidal anti-inflammatory drug relieved the ocular discomfort and hyperaemia, but the nodules regressed only partially and at no point resolved. This dissociation between symptomatic relief and persistence of the lesions was, in retrospect, the earliest argument against a purely inflammatory process. The initial work-up pointed toward inflammatory and granulomatous causes: elevated serum angiotensin-converting enzyme and lysozyme raised the possibility of sarcoidosis, although thoracic computed tomography, bronchoscopy and a first conjunctival biopsy performed without a lymphoma-directed panel were unrevealing, showing only reactive lymphoid hyperplasia. Approximately one year later, recurrent and now bilateral disease prompted a repeat biopsy with directed immunohistochemistry, which demonstrated a CD20-positive small B-cell infiltrate co-expressing CD5 and CD23 with negative cyclin D1 and CD10, consistent with chronic lymphocytic leukaemia/small lymphocytic lymphoma. Systemic staging with ¹⁸F-FDG PET/CT and bone marrow biopsy revealed no definite extra-conjunctival disease. After multidisciplinary review of observation, local radiotherapy and surgical excision, systemic therapy was preferred given the bilateral, recurrent and symptomatic course, and oral ibrutinib 420 mg once daily achieved complete clinical regression at three months and a sustained ocular response at two years, with indefinite haematological and ophthalmological surveillance planned. Full article

Endometrial cancer (EC) is a common gynecologic malignancy arising from the epithelial cells of the endometrium. The marked cellular heterogeneity of EC and features of its tumor immune microenvironment (TIME) contribute to disease complexity and have been associated with poor prognosis. This study integrates single-cell RNA sequencing, spatial transcriptomics, and Mendelian randomization (MR) to identify candidate genes associated with EC. Single-cell analysis identified MM0 as a putative stemness-associated transcriptional subpopulation with the highest CytoTRACE-inferred score; irGSEA indicated enrichment of proliferation- and stress-response pathways. Spatial data were analyzed with RCTD, MISTy, and stLearn to estimate spatial associations and pathway activities. MR and colocalization analyses integrating eQTL data and EC GWAS summary statistics prioritized DNAJA4, HSPA6, and LMNA as candidate genes with potential causal associations with EC risk. The expression patterns of these candidate genes were further examined in patient-derived samples. In Ishikawa cells cultured under high-estrogen conditions, siRNA-mediated knockdown of DNAJA4 and HSPA6 significantly suppressed proliferation and migration, accompanied by reduced CDK1 and Cyclin B expression. Collectively, these findings provide insight into EC heterogeneity and support further mechanistic investigation of candidate genes associated with malignant epithelial proliferation. Full article

Background/Objectives: Colorectal cancer (CRC) remains a major cause of cancer-related mortality worldwide, largely owing to metastasis, recurrence, and resistance to conventional therapies. Natural-product-derived compounds represent an important source of anticancer drug candidates. This study investigated the anticancer activity of purified narciclasine, which was tentatively annotated as a major detected constituent of Lycoris sanguinea extract, and examined its association with HELLS-associated DNA damage responses in CRC cells. Methods: Human CRC cell lines HT29 and HCT116 were used to evaluate the cytotoxic and mechanistic effects of L. sanguinea extract and narciclasine. Cell viability, clonogenic growth, apoptosis, mitochondrial membrane potential, cell cycle distribution, migration, and invasion were assessed. Western blotting was performed to analyze apoptosis-, cell cycle-, epithelial–mesenchymal transition (EMT)-, and DNA damage-related proteins. UPLC-QTOF/MS analysis was used to identify major phytochemical constituents. HELLS knockdown and γ-H2AX immunofluorescence staining were conducted to examine the involvement of HELLS in narciclasine-associated DNA damage and apoptosis. Results: L. sanguinea extract reduced CRC cell viability, suppressed clonogenic growth, induced mitochondrial dysfunction and caspase-dependent apoptosis, and promoted G2/M cell cycle arrest with decreased cyclin B1 and increased p53/p21 expression. The extract also inhibited migration and invasion, accompanied by reduced β-catenin, N-cadherin, vimentin, slug, and snail expression and increased E-cadherin expression. UPLC-QTOF/MS tentatively annotated narciclasine as a major detected constituent. Purified narciclasine recapitulated several anticancer effects of the extract, accompanied by HELLS downregulation, increased γ-H2AX accumulation, reduced cyclin B1 expression, and enhanced PARP and caspase-3 cleavage. HELLS knockdown further sensitized CRC cells to narciclasine-associated γ-H2AX accumulation, G2/M arrest-associated signaling, and apoptosis. Conclusions: Narciclasine treatment was associated with HELLS downregulation, DNA damage-associated signaling, G2/M cell cycle arrest-associated changes, EMT suppression, and apoptosis in CRC cells. These findings suggest that narciclasine is a promising natural-product-derived lead compound for further preclinical evaluation in HELLS-associated CRC vulnerabilities. Full article

Mammalian hearts exhibit limited regeneration, whereas zebrafish hearts present a remarkable capacity to regenerate upon injury through cardiomyocyte (CM) proliferation. Thus, understanding genes and especially transcription factors (TFs) enabling zebrafish CM regeneration may open new avenues for human heart repair. Herein, we injured zebrafish hearts by apex resection (AR) and found that the number of cycling CMs peaked around 7–14 days post-injury (dpi). Single-photon confocal imaging of 3D zebrafish hearts confirmed cycling cardiac cells throughout the heart at 7 dpi, while flow cytometry estimated that 1–2% of CMs were cycling. High-resolution single-cell RNA sequencing identified a CM cluster exclusively present after AR, whereas differential gene expression profiling identified genes defining this AR-specific CM cluster. Yet, overexpression of a single gene hit, Anxa2a, in mouse CMs did not override the inability of mammalian CMs to re-enter cell cycling. Instead, we outlined predicted upstream TFs responsible for the observed gene expression profile in the AR-specific CMs and, by proof-of-concept, overexpressed two predicted TF hits, Insm1 (Insulinoma-associated protein 1) and Tead1 (TEA Domain transcription factor 1) in mouse CMs. Notably, both Insm1 and Tead1 doubled the number of cycling mouse CMs, and despite that this induction was modest, CyclinB1 and Aurkb levels increased, pointing towards mouse CM division rather than a stimulation of polyploidy. In summary, we provide a new network of TFs predicted to regulate an AR-specific CM population in zebrafish that may be further explored to unravel zebrafish heart regeneration and eventually utilized for inducing CM proliferation in the mammalian heart. Full article

In this study, emodin was used as the starting material to synthesize two novel ligands, L1 and L2, containing bipyridine or phenanthroline moieties. Seven metal complexes (1–7) were obtained through coordination with Co, Rh, Ru, and Pt ions. Their structures were confirmed via NMR, HRMS, UV–Vis, IR, HPLC and SC-XRD analyses. The MTT assay showed that L1 and complex 2 selectively inhibited HepG-2 cells, with IC₅₀ values of 8.77 μM and 6.10 μM, respectively. Both compounds exhibited stronger activity than cisplatin (9.05 μM) and low toxicity toward normal 293T cells. Mechanistic studies demonstrated that they induced G2/M phase arrest by regulating Cyclin B1 and P21 expression, which was accompanied by ROS and Ca²⁺ accumulation, mitochondrial membrane potential disruption, and activation of the Caspase-9/3 cascade. Complex 2 showed superior antitumor activity to L1, and this finding was further supported by molecular docking analysis. In sum, Rh(III) complex 2 was identified as a selective and mechanistically defined anti-hepatocellular carcinoma lead compound, providing a potential strategy for the development of natural product-based metal anticancer agents. Full article

The RNA-binding proteins Musashi1 and Musashi2 (MSI1 and MSI2) regulate stem cell function and tissue plasticity by modulating mRNA translation. While typically known as translational repressors, the MSI1 and MSI2 proteins can also act as context-dependent activators of mRNA translation, although the mechanism of MSI-mediated translational activation is unknown. Here, we identify Embryonic Lethal Abnormal Vision-like (ELAVL) proteins as essential co-regulators of MSI1-dependent translational activation. In Xenopus laevis oocytes, antisense oligonucleotide knockdown of Elavl4 inhibited progesterone-stimulated maturation and blocked polyadenylation and translation of key MSI target mRNAs, including the Mos and Cyclin B5 mRNAs. Exogenous expression of ELAVL4 rescued these defects, confirming its necessity for maturation and cell cycle progression. Mechanistically, we determined that the ELAVL4 C-terminal domain interacts with the N-terminal RNA recognition motifs of MSI1 in an RNA-independent manner. Mass spectrometry and functional assays revealed this interaction is evolutionarily conserved: mouse ELAVL1 interacts with MSI1 in the pituitary, and human ELAVL1 rescues Elavl4-depleted Xenopus oocytes. Furthermore, knockdown of Elavl1 in a mammalian cell line abrogated MSI-dependent translational activation of a pituitary Prop1 3′ UTR mRNA reporter. Our results establish a conserved mechanism where ELAVL family members interact with MSI to promote MSI-dependent mRNA translational activation. Full article

Background: PRMT5, or protein arginine methyltransferase 5, is recognized as an epigenetic regulator that suppresses gene transcription through symmetric dimethylation of histone arginine residues, including histone H4 arginine 3 (H4R3me2s) and histone H3 arginine 8 (H3R8me2s), modifications associated with chromatin condensation and transcriptional repression. PRMT5-mediated methylation has been associated with recruitment of polycomb repressive complex 2 (PRC2) and enhancer of zeste homolog 2 (EZH2)-mediated H3K27me3 deposition, contributing to stable repression of tumor suppressor genes and apoptosis-related effectors in breast cancer. Methods: The molecular and functional impacts of PRMT5 inhibition were studied in TNBC cell lines with a pharmacological inhibitor (CMP5). Cellular responses were evaluated using a viability assay, qPCR, Western blotting, Annexin V/PI staining, and transwell migration/proliferation assays. Results: PRMT5 inhibition substantially reduced TNBC viability in a time- and dose-dependent manner. EZH2 was downregulated, whereas the tumor suppressor retinoblastoma-like protein 2 (RBL2) was induced, concomitant with low expression of Cyclin D1. These changes were accompanied by upregulation of pro-apoptotic effectors (Caspase-3, Caspase-10, death-associated protein 1 (DAP1), and BCL2-associated x protein (BAX) and repression of the pro-survival B-cell lymphoma 2 (BCL2), consistent with apoptosis-associated molecular responses. Functionally, CMP5 treatment was associated with reduced migratory behavior in TNBC cells under the experimental conditions tested. Conclusions: These findings suggest that PRMT5 inhibition by CMP5 is associated with reduced TNBC cell viability, impaired migration, increased expression of apoptosis-associated regulators and enhanced apoptotic cell death as measured by Annexin V/PI analysis in vitro. Further mechanistic and in vivo studies are required to clarify the therapeutic relevance of PRMT5 inhibition in TNBC. Full article

Cerebellar climbing fiber–Purkinje cell (CF–PC) long-term depression (LTD) plays a critical role in motor learning and is modulated by locus coeruleus (LC) noradrenergic afferents via distinct adrenergic receptor (AR) subtypes. Nevertheless, the mechanisms underlying LC noradrenergic neuron-mediated regulation of CF–PC LTD remain poorly understood. Here, we investigated the effects of chemogenetic activation of LC noradrenergic afferents on CF–PC LTD in cerebellar slices from dopamine β-hydroxylase (DBH)-Cre mice using electrophysiology, glutamate sensor imaging, immunofluorescence and pharmacological approaches. Tetanic stimulation (5 Hz) of CFs induced CF–PC LTD under control conditions, and this LTD was enhanced by chemogenetic activation of LC noradrenergic afferents. Blockade of group I metabotropic glutamate receptors (mGluR1) abolished LTD under control conditions, whereas chemogenetic activation of LC noradrenergic afferents triggered a novel form of CF–PC LTD accompanied by an increased N2/N1 ratio. With mGluR1 blocked, chemogenetic activation of LC noradrenergic afferents failed to trigger the novel CF–PC LTD following blockade of α₂-AR or α₂A-AR, but not α₂B-AR or α₂C-AR. Importantly, chemogenetic activation of LC noradrenergic afferents triggered LTD of glutamate fluorescence at CF terminals, which was abolished by blockade of α_2-AR or α₂A-AR, but not α₂B-AR or α₂C-AR. Notably, inhibition of either cyclin-dependent kinase 5 (CDK5) or presynaptic, but not postsynaptic, protein kinase A (PKA) completely abolished the CF–PC LTD triggered by chemogenetic activation of LC noradrenergic afferents in mouse cerebellar slices. Immunofluorescence results showed robust α₂A-AR expression throughout the cerebellar molecular layer, with intense signals along PC dendrites and clear colocalization with vesicular glutamate transporter 2 (vGluT2) at cerebellar CF terminals. These results indicate that activation of LC noradrenergic afferents potentiates CF–PC LTD by triggering Glu-LTD at CF terminals through the α₂A-AR/CDK5/PKA signaling cascade in the mouse cerebellar cortex. Full article

Resistance to combined BRAF and MEK inhibition remains a major barrier to durable disease control in BRAF-mutant melanoma. Acyclic retinoid (ACR; peretinoin) is a clinically studied retinoid, but its activity in MAPK inhibitor-resistant melanoma remains incompletely defined. Here, we established A375P-derived dabrafenib plus trametinib-resistant clones and evaluated ACR mainly in the A375PDTR-D clone as an in vitro proof-of-concept model. Resistant clones retained higher viability and failed to suppress ERK phosphorylation under dabrafenib plus trametinib treatment. In A375PDTR-D cells, ACR reduced short-term viability and clonogenic growth and was associated with decreased STAT3 Tyr705 phosphorylation, reduced EGFR, Cyclin D1, and Cyclin B1 expression, and increased p27KIP1. ACR did not detectably suppress AKT, MEK/ERK, or basal JNK phosphorylation under the tested conditions. These findings support further investigation of ACR as a candidate non-MAPK adjunct strategy; however, generalizability to broader melanoma models, formal drug-interaction status, direct cell-cycle/apoptosis effects, clinically achievable exposure, and in vivo efficacy remain to be established. Full article

Background: The dysregulation of the CDK1/Cyclin B1 complex drives tumor progression in breast cancer (BC). The natural flavonoid luteolin (LT) shows anti-cancer potential, but its mechanism targeting CDK1/CCNB1 remains unclear. Methods: CDK1, CCNB1, and CCNB2 expression were profiled in normal and BC cell lines. An engineered HEK293T GST-CDK1/CCNB1 cell model was used to evaluate LT’s effects on proliferation, ROS levels, and target gene transcription. Computational approaches (molecular docking, dynamics simulations, pharmacophore modeling, MM/GBSA, ADMET, and network pharmacology) assessed LT and its analogues. Results: CDK1/CCNB1 expression was lower in MCF7 BC cells than in normal cells, suggesting the loss of a growth barrier. In engineered HEK293T cells, LT suppressed CCNB1 transcription with minimal effect on CDK1 levels, correlating with anti-proliferative and ROS-modulating effects. Computational analyses confirmed stable LT binding to the CDK1/CCNB1 complex. Designed LT analogues showed improved binding and favorable ADMET profiles. Network pharmacology identified cell cycle regulation, particularly in BC stem cells, as the primary pathway targeted. Conclusions: LT and its analogues inhibit the CDK1/Cyclin B1 complex, revealing a dual mechanism that suppresses both tumor growth and BC stemness. Full article

Hepatocellular carcinoma is one of the most aggressive malignancies worldwide, with limited therapeutic options. Boswellia serrata Roxb., an Indian medicinal tree, produces a resin rich in essential oil and boswellic acids, particularly acetyl-11-keto-β-boswellic acid (AKBA), with demonstrated antiproliferative and pro-apoptotic activities. This study investigated the cytotoxic effects of B. serrata essential oil and AKBA on hepatocarcinoma Huh-7 cells in both monolayer and three-dimensional spheroid cultures and characterized the underlying molecular targets. Essential oil was extracted and analyzed by gas chromatography-mass spectrometry (GC-MS). Cytotoxicity was assessed using the cell counting kit-8 (CCK-8). Three-dimensional spheroid cultures were also established to evaluate anti-tumoral potential. Expression of cyclin D1, cyclin-dependent of kinase 4 (CDK4) (cyclin-dependent kinase inhibitor 1A (p21), E-cadherin, (alpha fetoprotein) AFP, epithelial cell adhesion molecule (EpCAM), Myeloid cell leukemia-1 (Mcl-1), and caspase-3 was analyzed by western blot. In addition, an in silico analysis was performed on the main constituents of B. serrata essential oil targeting 5-lipoxygenase (5LO). The results showed cytotoxic effects, with AKBA exhibiting greater potency than the essential oil. Cytotoxicity was associated with caspase-3-mediated apoptosis, with minimal effects on cell cycle and epithelial–mesenchymal transition markers. The in silico analysis predicted that some compounds may act as competitive inhibitors of the 5LO at the catalytic site and partially activate pro-apoptotic pathways. These data support the potential of B. serrata-derived compounds as novel anti-hepatocarcinoma agents, with AKBA and longifolene as leads for further preclinical and clinical research. Full article

Background/Objectives: Colorectal cancer (CRC) remains one of the leading causes of cancer-related morbidity and mortality worldwide. Despite advances in treatment, outcomes for advanced CRC remain unsatisfactory due to uncontrolled proliferation, metastasis, and recurrence. This study investigated the anti-cancer effects of KMU-11342, an indolin-2-one-based multi-protein kinase inhibitor with previously reported anti-inflammatory properties, in human colorectal cancer models. Methods: The anti-cancer effects of KMU-11342 were evaluated in colorectal cancer cells and further investigated in three-dimensional (3D) spheroid and patient-derived organoid models. Cell proliferation, migration, apoptosis, and cell cycle progression were assessed. Kinase activity profiling and molecular docking analyses were performed to identify potential targets and characterize the underlying signaling pathways. Results: KMU-11342 significantly inhibited the proliferation and migration of CRC cells. It reduced CRC cell density by 58.9% and 83.3% at 0.5 and 1 μM, respectively. These effects were accompanied by G2/M cell cycle arrest and apoptotic cell death. In 3D models, spheroid formation was markedly reduced and stemness-related characteristics were diminished. Patient-derived CRC organoids also showed decreased viability, exhibiting 38.6% and 77.4% reductions at 1 and 2 μM, respectively. These effects were observed in a dose-dependent manner in both two-dimensional (2D) and 3D colorectal cancer models. Kinase activity profiling and molecular docking analyses identified glycogen synthase kinase 3 beta (GSK3β) and cyclin-dependent kinase 1 (CDK1) as potential mediators of the anti-cancer effects of KMU-11342 through the p53/nuclear factor kappa B (NF-κB) and FoxO1 signaling axes, respectively. Conclusions: KMU-11342 exhibits potent anti-tumor activity against CRC through suppressing proliferation, migration, and stemness in both 2D and 3D models, including patient-derived organoids. Its effects may be mediated, at least in part, through modulation of GSK3β and CDK1 via the p53/NF-κB and FoxO1 signaling pathways. Full article

New copper(II) (C1) and palladium(II) (C2) complexes with S,O-tetradentate ligand (L) derived from thiosalicylic and thiopropionic acids were synthesized. In cell-based assays, (C1) exhibited the most pronounced activity within the tested compound series and was therefore advanced for mechanistic evaluation in 4T1 triple-negative breast cancer cells. (C1) significantly reduced 4T1 cell viability by inducing early and late apoptosis, accompanied by mitochondrial membrane depolarization and enhanced cytochrome C release. Consistently, (C1) increased the Bax/Bcl-2 ratio, promoting a pro-apoptotic shift. In parallel, (C1) triggered autophagy, as evidenced by decreased p62 and LC3B levels, induced G0/G1 cell-cycle arrest, and suppressed proliferative signaling by downregulating Ki67, cyclin D, and phosphorylated AKT. The DNA-binding studies showed moderate to strong affinity, favoring minor groove binding, with higher affinity for (C1) than for (C2). Tryptophan fluorescence quenching indicated a strong interaction with BSA via a predominantly static mechanism, more pronounced for (C1). Molecular docking at the DNA and BSA binding sites corroborated experimental findings and suggested favorable interactions between the complexes and apoptosis-related proteins (CASP3, BAX, and BCL2). The integrated experimental and computational data identify (C1) as a biologically active compound with multimodal biological effects in vitro, supporting further structural optimization and mechanistic investigation. Full article

Natural therapeutic alternatives are increasingly explored in endometriosis, a highly prevalent gynecological disorder with limited therapeutic options. Rosmarinus officinalis (rosemary) has attracted increasing scientific interest due to its biological activity. This study aimed to characterize a hydroethanolic rosemary extract (RE) and evaluate its effects on key cellular processes involved in endometriosis pathophysiology. Major phenolic compounds in RE were quantified by RP-HPLC, and antioxidant activity was assessed using DPPH, ABTS, and FRAP assays. After RE treatment, cell viability (WST-1), migration (wound healing assay), cell cycle distribution (DAPI staining), apoptosis (Annexin V/PI), p21 and cyclin A expression (Western blot), and intracellular ROS levels (DCFH-DA) were evaluated in endometrial stromal (t-HESC, St-T1b) and endometriotic epithelial (12-Z) cells. Phytochemical analysis revealed rosmarinic acid (RA) at 4.2%, while carnosic acid (CA) and carnosol (CS) together accounted for 23.7% of the extract. RE reduced cell viability and cell migration in 12-Z and t-HESC cells (p < 0.05). S-phase accumulation with a concomitant reduction in the G1 phase was observed across all evaluated cell lines (p < 0.05), along with increased p21 and cyclin A expression in stromal cells (p < 0.05). RE induced cell death in both 12-Z (p < 0.05) and St-T1b cells (p < 0.0001). In t-HESC cells, RE reduced both basal and H₂O₂-induced ROS levels (p < 0.01). These findings indicate that RE modulates key mechanisms involved in endometriosis pathophysiology, supporting its multi-target therapeutic potential as a nutraceutical approach for endometriosis management. Full article