The olive family, Oleaceae, is a diverse and widely distributed group of flowering plants that encompasses a rich variety of species with significant ecological, economic, and cultural importance. Oleuropein (OLE) is the most abundant polyphenolic compound in olive leaf extract that exhibits a broad spectrum of pharmacological activities, including antioxidant, anti-inflammatory, anti-tumor, anti-apoptotic, and anti-autophagic effects. These properties render it a promising compound for a wide range of applications. This review summarizes recent research on the potential applications of OLE in disease treatment, with particular emphasis on its underlying mechanisms, including antioxidant activity, regulation of endogenous redox-related enzymes, modulation of key inflammatory signaling pathways, and suppression of pro-inflammatory cytokine production. In addition, this review discusses the latest clinical trials involving OLE and its potential as an adjunct treatment.

Cyclopiazonic acid (CPA), a neurotoxin produced by Penicillium and Aspergillus genera, induces oxidative stress and neuronal damage, mechanisms implicated in neurodegenerative diseases. This study investigates the oxidative stress induced by CPA in SH-SY5Y human neuroblastoma cells, focusing on mitochondrial membrane potential, mitochondrial superoxide levels, ROS production, lipid peroxidation and gene expression. Additionally, the cytoprotective effects of extra virgin olive oil (EVOO) extract, along with its major polyphenols oleuropein (OLE) and tyrosol (TYR), were evaluated. CPA exposure increased mitochondrial superoxide levels and lipid peroxidation, reducing mitochondrial membrane potential, although no intracellular ROS generation was observed. Gene expression analysis revealed downregulation of antioxidant defense genes (nrf2, nos2, ho1, cat, keap1, nqo1, gpx1 and gsr), with the strongest repression observed for nos2 (93%), nqo1 (83%) and ho1 (79%) at the highest CPA concentration, consistent with oxidative stress markers. EVOO extract demonstrated protective effects, enhancing cell viability across all CPA assayed concentrations (400-600 nM). Conversely, TYR and OLE exhibited variable and concentration-dependent effects, also showing protection to a lesser extent, while EVOO extract proved to be more effective due to synergistic interactions among its phenolic components. Overall, CPA induces mitochondrial oxidative damage as a key mechanism of neurotoxicity, while EVOO phenolics mitigate this toxicity.

Cardiac fibrosis is a key pathological feature of diabetic cardiomyopathy (DCM), contributing to progressive cardiac dysfunction. Transforming growth factor beta-1 (TGF-β1), via Smad2/3 signaling pathway, promotes fibrotic gene expression. Oleuropein (OL), a major phenolic constituent of olive products, exhibits significant antioxidant properties and contributes to cardiovascular protection. This study aimed to investigate the anti-fibrotic effects of OL in a rat model of DCM and its modulation of the TGF-β1/Smad signaling pathway, using Losartan as a positive control. Thirty-two male Wistar rats were randomly assigned to four groups: control, DCM, DCM + OL (40 mg/kg), and DCM + Losartan (10 mg/kg). DCM was induced via high-fat diet (HFD) and a single low-dose streptozotocin (STZ) injection (40 mg/kg). Cardiac function was assessed by echocardiography. Histological evaluation included hematoxylin-eosin (H&E) and Masson trichrome staining. Cardiac biomarkers, oxidative stress markers, and fibrosis-related markers were analyzed using RT-qPCR, immunohistochemistry, and western blotting. DCM rats exhibited cardiac dysfunction and fibrosis. OL treatment significantly improved cardiac function, reduced collagen and fibronectin (FN) deposition, and downregulated TGF-β1, Smad2/3, α-smooth muscle actin (α-SMA), collagen types I/III, matrix metalloproteinases-2/9 (MMPs), and tissue inhibitor of metalloproteinases-1 (TIMP-1), while enhancing Smad7 expression. Besides, OL demonstrated notable antioxidant and antidiabetic effects. In conclusion, OL alleviates cardiac fibrosis and dysfunction in DCM, potentially through modulation of the TGF-β1/Smad signaling, highlighting its therapeutic promise in diabetic cardiac complications.

teroid-induced osteonecrosis of the femoral head (SONFH) is a severe bone disorder caused by long-term glucocorticoid administration and is characterized by osteoblast apoptosis. Oleuropein (OLP), a natural compound with anti-inflammatory and antioxidant properties, has demonstrated anti-apoptotic potential in bone-related diseases. However, its therapeutic role in SONFH has not yet been elucidated. This study aimed to investigate the therapeutic effects of OLP on SONFH and elucidate its underlying molecular mechanisms. In vitro, MC3T3-E1 osteoblasts treated with methylprednisolone (MPS) were co-incubated with OLP. Cell viability was assessed using a CCK-8 assay and live/dead cell staining. In vivo, a rat SONFH model was established with lipopolysaccharide and MPS, followed by OLP treatment. Bone microstructure was analyzed by micro-computed tomography and histopathological staining (H&E, Masson, Goldner). Network pharmacology and proteomics analyses were used to identify key targets and pathways related to the effects of OLP on SONFH. Apoptosis was examined with flow cytometry, TUNEL staining and ELISA. Protein and mRNA expression levels of relevant targets and pathways were examined with western blotting and quantitative real-time polymerase chain reaction. OLP significantly reversed MPS-induced osteoblast apoptosis and enhanced cell viability. In SONFH rats, OLP reduced empty lacunae, restored trabecular bone structure, and improved collagen organization. Molecular docking confirmed OLP's binding to AKT and Bcl2. Network pharmacology and proteomics highlighted apoptosis regulation, PI3K-AKT signaling, and cell cycle control as key mechanisms. Furthermore, OLP activated the PI3K-AKT-Bcl2 pathway, increasing p-PI3K, p-AKT, and Bcl2 levels while decreasing Caspase3 and Caspase9. OLP also promoted osteogenesis (upregulated ALP and Runx2) and angiogenesis (increased vWF and CD31). OLP alleviates SONFH by inhibiting osteoblast apoptosis and promoting osteogenesis and angiogenesis through activation of the PI3K-AKT-Bcl2 pathway. These findings support OLP as a promising natural compound for early intervention in SONFH.

Oleuropein restores oocyte competence during SIRT1 inhibition via SIRT1/NRF2-mediated redox and metabolic reprogramming in porcine oocytes.

Background and Aim This study assessed the renal toxicity of monosodium glutamate (MSG) and, for the first time, jointly examined the potential nephroprotective effects of the olive-derived compounds hydroxytyrosol (HT) and oleuropein (OLE) in an aged rat model. By doing so, it sought to address a notable gap in the existing literature by clarifying the protective roles of HT and OLE against MSG-induced renal injury. Experimental Approach A total of 60 aged male Sprague–Dawley rats (≥20 months old) were randomly allocated into six experimental groups. Control, MSG (600 mg/kg/day), HT (10 mg/kg/day), OLE (200 mg/kg/day), and combined treatment (MSG+HT/MSG+OLE) groups. All compounds were administered orally for 28 days. Kidney tissues were collected for biochemical and histopathological evaluation. Oxidative stress markers, antioxidant status, DNA damage, and apoptosis-related parameters were assessed, and histopathological alterations were examined using hematoxylin–eosin staining. Key Findings Significant intergroup differences (P < 0.05) were detected for all evaluated biochemical parameters, including Total Antioxidant Capacity, Total Oxidant Capacity, Oxidative Stress Index, 8-hydroxy-2′-deoxyguanosine, Malondialdehyde, Catalase, and Caspase-3. Histopathologically, MSG administration induced marked renal damage characterized by glomerular hypertrophy, mesangial cell proliferation, tubular epithelial degeneration, hyaline cast formation, vascular hyperemia, interstitial edema, and focal or extensive coagulative necrosis. In contrast, co-treatment with HT or OLE markedly reduced the severity and distribution of these lesions. Conclusion The findings confirm the nephrotoxic effects of MSG and demonstrate the nephroprotective properties of both HT and OLE in a rat model, indicating potential mechanisms through which these olive-derived compounds alleviate MSG-induced renal damage.

Among the diverse mechanisms driving cancer progression, dysregulated kinase signaling and immune evasion mechanisms are particularly critical, necessitating the development of therapies that simultaneously target kinase-dependent tumor survival pathways and reinvigorate antitumor immunity. Oleuropein (OP), a natural polyphenol with established chemopreventive activity, exhibits limited potency and bioavailability. To overcome these limitations, a series of structurally optimized semi-synthetic OP analogs were developed and screened for their anticancer activity. The most prominent, Ole-4, was further evaluated for its antitumor mechanism of action. Ten OP analogs were screened against a panel of human and mouse cancer cell lines. The most active, Ole-4 was further assessed for its cytostatic and pro-apoptotic effects in breast cancer cells using proliferation assays, cell-cycle analysis, and apoptosis quantification. Kinome profiling was performed to identify alterations in protein tyrosine (PTK) and serine/threonine (STK) kinase activity induced by Ole-4. C57BL/6J mice bearing subcutaneous B16.F1 melanoma tumors and BALB/c mice bearing CT26 colon and D2F2/E2 breast carcinomas, were treated intraperitoneally with Ole-4 to evaluate its in vivo efficacy. Immune activation and tumor infiltration by effector cells were analyzed by flow cytometry and immunohistochemistry. In vitro, the OP analog Ole-4 exhibited potent cytotoxicity against breast, ovarian, melanoma, cervical and colon carcinoma cell lines. Specifically in HER2+ breast cancer cells, Ole-4 significantly inhibited proliferation by inducing S-phase arrest and triggering apoptosis. These effects correlated with kinome profiling data, indicating sustained functional suppression of the STKs Akt and P70S6KB, key regulators of cell survival and growth. Likewise, Ole-4 reduced the activity of Src, ROCK1, and EphA2 kinases which are critically implicated in tumor metastasis, and enhanced the RAF/ERK and Jak1b signaling axes, closely linked to stress-adaptive responses. In vivo, Ole-4 suppressed melanoma, colon and breast carcinoma growth in mice subcutaneously inoculated with syngeneic B16.F1, CT26 and D2F2/E2 cancer cells. Additionally, Ole-4 generated immune cell-mediated antitumor cytotoxicity in treated mice, and importantly, increased tumor infiltration by cytotoxic T and natural killer cells. Our findings suggest that Ole-4 exerts direct anticancer effects, likely mediated via STK-dependent mechanisms, while indirectly it enhances immune effector responses, sensitizing tumor cells to immune-mediated apoptosis. Based on these tumor inhibitory and immunomodulatory properties, Ole-4 emerges as a promising candidate for designing next-generation anticancer drugs.

Oncological patients receiving radiotherapy or chemotherapy often experience impaired wound healing due to tissue damage and cellular senescence. Connexin43 (Cx43) is a key regulator in this process, promoting senescence and the SASP, which hinder regeneration. This study investigates targeting Cx43 in primary dermal fibroblasts from cancer patients using a new combination of nanoencapsulated drugs. We show that Cx43 overexpression correlates with reduced gap junction communication, increased senescence, and delayed healing. Treatment with oleuropein (OLP), a polyphenol with antioxidant and regenerative properties, restores fibroblast function, reduces senescence, and improves healing. We also examine the p38 MAPK inhibitor BIRB796, alone and with OLP, demonstrating its ability to suppress SASP and support tissue repair. After confirming the superior combined effect of OLP and BIRB796, we developed a co-encapsulated nanoformulation. This innovative approach may significantly enhance wound healing in oncological patients.

Objective: Parkinson’s disease (PD) and alcohol use disorder (AUD) have different clinical profiles, but they may share certain molecular weaknesses. This computer-based study explores the new idea that Glycophorin-E (GYPE) could be a common target for both conditions, with the natural compound oleuropein (OLE) as a possible modulator. Methods: Using structure-based computational methods, we conducted molecular docking and interaction analysis to examine how OLE binds to a modeled GYPE structure. Results: The analysis showed that OLE has a stable and energetically favorable binding position in a proposed active site of GYPE, with a binding strength of -5.3 kcal/mol. The complex’s stability comes from a mix of specific intermolecular forces, including important hydrophobic interactions with Val35 and Tyr39, along with essential hydrogen bonds with Ser30, Thr36, Tyr39, and Gln43. Importantly, Tyr39 plays a dual role by also forming a stabilizing salt bridge, adding notable ionic interaction energy that helps stabilize the overall complex. These findings present the first computer-based evidence for strong and specific binding of OLE to GYPE. Conclusion: We suggest that this interaction could explain how OLE shows neuroprotective and anti-addictive effects by influencing GYPE-related pathways. However, this study has limitations since it is a computer-based analysis. Also, because Glycophorin E is a protein with low biological expression, further in vivo and in vitro studies are needed to confirm its potential effects in the body.

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

Hepatic encephalopathy (HE), which develops as a result of liver failure, is an important neurological disorder involving inflammation and oxidative damage, with apoptosis and autophagy supported mainly by experimental evidence. In the current research, we researched the protective effects of oleuropein (OLE) in a thioacetamide (TAA)-induced HE model, particularly through the PI3K/Akt/mTOR signalling pathway. To execute the planned experimental design, Sprague Dawley rats (n = 28) were divided into four groups: Control, OLE, TAA, and TAA + OLE. OLE was administered orally (50mg/kg) during a 14-day period, followed by intraperitoneal TAA (50mg/kg) for 14 days in the TAA groups. Behavioral tests (open field and Y-maze) were used to determine cognitive and anxiety-like disorders in the rats. Oxidative stress indicators (MDA, SOD, and GSH), pro-inflammatory cytokines (IL-1β, IFN-γ, and TNF-α), autophagic and apoptotic processes (Caspase-3, Bcl-2, Beclin-1, LC3), PI3K/Akt/mTOR pathway proteins, and AQP4 levels were analyzed in the serum and tissue. Histopathological evaluation was used to evaluate tissue damage in the liver and brain. The results indicated that the TAA-activated PI3K/Akt/mTOR pathway was suppressed by OLE, oxidative damage, autophagy, apoptosis, and inflammation were reduced, and behavioral and histological improvements were achieved. These results suggest that OLE offers hepatoprotective effects and ameliorates HE-associated brain injury via the PI3K/Akt/mTOR pathway.

Investigating the interaction of cancer stem cells (CSCs) with the tumor microenvironment provides critical insights into their roles in promoting angiogenesis and metastasis through various cellular and molecular adaptation mechanisms, including survival, maintenance of stemness, dormancy, and treatment response. In the present study, we aimed to evaluate the biological responses of CSCs following targeted treatment with phenolic oleuropein (OLE), a glycosylated seco-iridoid compound, within a three-dimensional (3D) microenvironment. CD44⁺/CD24⁻/low CSCs were isolated from the MCF-7 cell line using magnetic-activated cell sorting (MACS). The expression levels of stemness-related genes (OCT3/4, NANOG, SOX2) and drug resistance markers (ABCG1, ABCG2) were assessed in both MCF-7 cells and CSCs using RT-qPCR and the spheroid structures were further evaluated using the TUNEL assay to assess apoptotic activity. CSCs exhibited significantly elevated expression of ABCG1 and stemness markers (OCT3/4, NANOG, SOX2) compared to parental MCF-7 cells. Following OLE treatment, both static and dynamic cultures demonstrated increased expression of OCT3/4, NANOG, SOX2, SURVIVIN, CYCLIN-D1, and p21. Notably, while untreated cells expressed ABCG1 and ABCG2, these genes were not detectable in OLE-treated cells under either culture condition. Collectively, these findings underscore the anti-proliferative and pro-apoptotic effects of OLE on CSCs and highlight its potential to counteract drug resistance mechanisms within a biomimetic 3D microenvironment.

Targeting KEAP1/NRF2 interaction with oleuropein ameliorates atherosclerosis by inhibiting macrophage ferroptosis.

Protective effects of oleuropein against monosodium glutamate-induced toxicity in aged rats.

Ultraviolet B (UVB) exposure induces skin photoaging through triggering oxidative stress, inflammation, apoptosis, and collagen degradation. Oleuropein (OLE), Hydroxytyrosol (HT), and Verbascoside (Verb) are polyphenols derived from olive leaves, exhibiting potent antioxidant and anti-inflammatory properties. In the present study, we investigated the protective effects of OLE, HT, and Verb combination (O/H/V) against UVB-induced photoaging using in vitro models. The results showed that O/H/V treatment reduced the expression of senescence and apoptosis-related markers, while concurrently downregulated inflammatory factors and matrix metalloproteinases via suppression of MAPK and NF-κB pathways in UVB-irradiated HDF cells. In UVB-irradiated HaCaT cells, O/H/V treatment attenuated collagen degradation and pro-inflammatory factors expression via upregulation of Nrf2 levels. Furthermore, in a HaCaT-HDFs co-culture system, treatment of UVB-irradiated HaCaT cells with the O/H/V combination led to a significant reduction in pro-inflammatory factors and collagen degradation-related genes in HDFs. Together, these findings indicate that the O/H/V combination exerts protection against UVB-induced photoaging through multiple mechanisms, including inhibition of MAPK/NF-κB pathway and enhancement of Nrf2 expression.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-24845-4.

This study addressed the fabrication of mesoporous polydopamine nanoparticles (MPD NPs) by an emulsion-induced interface assembly technique, followed by the incorporation of oleuropein (OLE) into MPD NPs via electrostatic attraction, resulting in OLE@MPD NPs. In the post-myocardial infarction (MI) context, these therapies were explicitly designed to eradicate reactive oxygen species (ROS) and promote MI healing. We additionally integrated them with a thermosensitive chitosan (CH) hydrogel (HGL) to generate an injectable composite hydrogel (OLE@MPD/CH HGL). Through in vitro tests, the OLE@MPD/CH HGL demonstrated remarkable ROS-scavenging capability in H9C2 cells subjected to oxidative stress and effectively inhibited their apoptosis. This study introduces an innovative method to enhance MI therapy by utilizing the OLE@MPD/CH HGL. This OLE@MPD/CH HGL efficiently diminishes localized oxidative stress caused by ROS and activates the HO-1/Nrf2 signaling pathway.

Oleuropein (OLE), as the main effective active component in olive leaves, is a natural cyclic ether terpene polyphenolic compound found in plants of the genus Olea. It has antioxidant, anti-inflammatory and anti-apoptotic properties, and can reduce damage caused by reactive oxygen species. These characteristics indicate that it can enhance the maturation rate of oocytes and the developmental capacity of embryos-two key indicators in animal breeding. This study evaluated the effects of OLE on the in vitro maturation and early embryonic development of sheep oocytes. 20 μM OLE has the best promoting effect on the maturation rate of oocytes, and 30 μM OLE has the best increasing effect on the blastocyst rate. Compared with the control group, glutathione (GSH) level and mitochondrial membrane potential (MMP) level were significantly increased, ROS level was significantly decreased, the expression of antioxidant genes SOD1 and GPX3 was significantly elevated, and the expression of anti-apoptotic gene BCL2 was significantly elevated in the experimental group. In addition, during the in vitro development stage of early embryos, the expression level of the embryo development-related gene OCT4 significantly increased. The study has shown that OLE can effectively alleviate oxidative stress during in vitro culture, increase oocyte maturation rate and promote embryo development.

The role of oleuropein (OLE) in K562 leukemia progression was investigated by evaluating its antiproliferative effect via the XTT assay, oxidative damage through 8-OHdG and TAS/TOS measurements, and apoptotic activity using Caspase-3 assays. Total RNA was isolated from control and treated cells, followed by cDNA synthesis and RT-PCR analysis to assess mRNA expression of DNA repair-related genes. OLE reduced K562 leukemia cell viability in a time- and dose-dependent manner, with an IC50 of 244 µM at 72 h. Treatment with OLE decreased both total oxidant and antioxidant status, while increasing the oxidative stress index. However, changes in 8-OHdG and Caspase-3 levels were not statistically significant. Additionally, no significant differences were observed in the expression of XRCC1, APE1, NEIL1, and PARP1 genes after 72 h of treatment with 244 µM OLE. These findings suggest that OLE may possess anticancer potential and could contribute to the development of therapeutic strategies for hematological malignancies such as leukemia.

From in silico design to in vitro validation: Surfactant free synthesis of Oleuropein loaded levan nanoparticles.

Glioblastoma (GB), the most aggressive type of brain tumor, has a poor prognosis. In this study, we aimed to develop a drug delivery system that can be used in GB treatment with the bioactive compounds oleuropein (OL) and its derivative hydroxytyrosol (HT) loaded into mesoporous silica nanoparticles (MSNs) and to investigate their anticancer effects on GB cells. MSNs were synthesized via a sol‒gel method, followed by surface grafting of azetidine to introduce hyperbranched polypropylene imine (PPI) groups, increasing the particle stability and OL/HT loading efficiency. OL and HT-loaded MSN-PPI nanocarriers (MSN-PPI@OL and MSN-PPI@HT) were characterized, and their effects on tumor aggressiveness were evaluated in T98G cells. The results showed that the nanocarriers presented a positive surface charge and hydrodynamic sizes between 300 and 500nm, with effective concentrations above 100µg/mL. MSN-PPI@OL and MSN-PPI@HT alone and in combination with temozolomide (TMZ) inhibited cell migration (p < 0.0001), reduced the expression of epithelial‒mesenchymal transition (EMT) markers (p < 0.05), and suppressed angiogenesis (p < 0.0001). In the colony formation assays, the MSN-PPI nanocarriers had stronger antiproliferative effects than did TMZ (p < 0.0001) and suppressed the expression of stem cell markers (p < 0.05). Additionally, these treatments decreased LOXL1-AS1, PVT1, and MALAT1 expression (p < 0.05) and reduced global cell viability (p < 0.0001). In conclusion, these findings suggest the potential of MSN-PPI@OL and MSN-PPI@HT as effective therapeutic strategies for GB.