Pharmaceuticals最新文献

{"title":"Enhancing the Antitumor Efficacy of Nisin Through Advanced Nanosystems: A Systematic Review of In Vitro Studies.","authors":"Mariatta Ceballos Benavides, Julián Castillo Muñoz, Karol Marcillo Villota, Sinthia Vidal Cañas, Alberto Aragón-Muriel, Jorge A Egurrola-Pedraza, Yamil Liscano","doi":"10.3390/ph19040611","DOIUrl":"10.3390/ph19040611","url":null,"abstract":"<p><p><b>Background and Objectives:</b> While nisin exhibits promising antitumor properties, its clinical utility is hindered by pharmacokinetic instability and rapid enzymatic degradation. This systematic review evaluates the critical role of advanced pharmaceutical formulations and targeted nanosystems in overcoming these limitations to enhance nisin's cytotoxic and pro-apoptotic efficacy in vitro. <b>Methods:</b> Following PRISMA guidelines, a comprehensive search was conducted across six electronic databases (PubMed, ScienceDirect, Scopus, Web of Science, SpringerLink, and DOAJ). In vitro studies comparing free nisin against polymeric, metallic, and cyclodextrin-based nanocarriers across diverse neoplastic lineages were included. Methodological quality was assessed using the SciRAP 2.1 tool, and a within-line comparative analysis was performed for MDA-MB-231 and HT-29 models. <b>Results:</b> Twelve studies met the inclusion criteria. A definitive technological inflection point was identified: nisin-loaded nanosystems reduced effective concentrations by up to 2706-fold relative to the free peptide in MDA-MB-231 cells, and 71-fold in A549 lung cancer cells. Mechanistically, nanosystems facilitated membrane pore formation, mitochondrial-mediated apoptosis via Bax/Bcl-2 modulation, caspase 3/7/9 activation, and p53 reactivation. Three previously underreported mechanistic dimensions were identified: TWIST1 downregulation and FZD7 binding in hepatocellular carcinoma, and downregulation of CEA, CEAM6, MMP2F, and MMP9F in colorectal cancer lines. <b>Conclusions:</b> The therapeutic viability of nisin in oncology is strictly dependent on pharmaceutical engineering. Future research must prioritize in vivo pharmacokinetic validation, experimental confirmation of novel mechanistic targets, and standardized nisin purity reporting to consolidate its clinical translation.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"19 4","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13118593/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147819893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Danggui Buxue Tang, a Traditional Chinese Herbal Formula, Potentiates Paclitaxel Efficacy in Non-Small-Cell Lung Cancer by Inducing Ferroptosis via the Nrf2/GPX4 Axis.","authors":"Guowei Gong, Tianpeng Yin, Zhenxia Zhang, Kumar Ganesan, Yuzhong Zheng","doi":"10.3390/ph19040607","DOIUrl":"10.3390/ph19040607","url":null,"abstract":"<p><p><b>Background/Objectives:</b> Non-small-cell lung cancer (NSCLC) involves oxidative stress and inflammation, driving chemoresistance. Paclitaxel (PTX), a first-line chemotherapy, is limited by these factors. Danggui Buxue Tang (DBT), a polyphenolic-rich traditional Chinese herbal formula, was investigated for its ability to potentiate PTX efficacy by inducing ferroptosis via the Nrf2/GPX4 axis. <b>Methods:</b> Effects of DBT + PTX on cell viability, lipid peroxidation, iron accumulation, and Nrf2/GPX4/SLC7A11 expression were evaluated in A549/HCC827 cells with/without ferrostatin-1 (Fer-1). Findings were validated in an A549 xenograft model. <b>Results:</b> DBT significantly enhanced PTX's anti-tumor effects in vitro and in vivo, an effect reversed by Fer-1. Combination therapy increased ROS, MDA, and iron while suppressing GPX4/SLC7A11 and promoting Nrf2 nuclear translocation. DBT + PTX synergistically reduced tumor volume and proliferation markers (Ki67/PCNA). Crucially, DBT attenuated PTX-induced hepatotoxicity and nephrotoxicity. <b>Conclusions:</b> DBT potentiates PTX efficacy in NSCLC by disrupting the Nrf2/GPX4 axis to induce ferroptosis while mitigating chemotherapy-related toxicity, supporting its potential as an adjuvant strategy targeting oxidative stress pathways.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"19 4","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13118578/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147819878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CDK4/6 Inhibitors for Breast Cancer Therapy-A Review of Clinical Trials, Structural and Computational Approaches.","authors":"Adela Avdičević, Samo Lešnik, Urban Bren, Luka Čavka","doi":"10.3390/ph19040610","DOIUrl":"10.3390/ph19040610","url":null,"abstract":"<p><p>Cyclin-dependent kinases 4 and 6 (CDK4/6) play a central role in the regulation of cell cycle progression and represent important therapeutic targets in hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer. The introduction of selective CDK4/6 inhibitors, including palbociclib, ribociclib, and abemaciclib, in combination with endocrine therapy, has significantly improved clinical outcomes and has become a standard treatment strategy in both metastatic and high-risk early-stage disease. Nevertheless, treatment resistance and disease progression remain major clinical challenges. A deeper understanding of the structural characteristics of CDK4/6 and the molecular basis of inhibitor binding is therefore essential for improving therapeutic strategies and guiding the development of new targeted agents. This review provides an integrated overview of the structural features of CDK4/6 and their role in cell cycle regulation, summarizes the clinical development and major clinical trials of currently approved CDK4/6 inhibitors, and discusses recent computational studies investigating inhibitor binding and conformational dynamics. Particular attention is given to the application of in silico approaches, including molecular docking, molecular dynamics simulations, and binding free-energy calculations, which provide insights into mechanisms of therapy resistance and potential strategies to overcome them and support the identification and optimization of novel CDK4/6-targeted therapeutic candidates. By integrating structural, clinical, and computational perspectives, this review highlights current knowledge and emerging directions in CDK4/6 research that may advance the development of more personalized therapies for HR+/HER2- breast cancer, while accounting for both intrinsic and de novo resistance mechanisms.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"19 4","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13118760/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147819710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of an Empirical Approach for the Prediction of Cytochrome P450-Based Drug-Drug Interactions in Pediatric Patients.","authors":"Veronica Di Paolo, Francesco Maria Ferrari, Italo Poggesi, Luigi Quintieri","doi":"10.3390/ph19040608","DOIUrl":"10.3390/ph19040608","url":null,"abstract":"<p><p><b>Background and Objective</b>: Predicting drug-drug interactions (DDIs) in pediatric patients remains a major challenge in clinical pharmacology. This study aimed to evaluate and compare three empirical approaches for extrapolating adult cytochrome P450 (CYP)-mediated DDI pharmacokinetics (PK) data to predict the extent of the corresponding DDIs in children across different age groups. <b>Methods</b>: The approaches assessed were: (A) the direct use of adult area under the plasma concentration-time curve ratios (AUCRs) as estimators of pediatric values; (B) the application of a correction accounting for the ontogeny of the involved CYP enzyme; and (C) the application of corrections for both enzyme ontogeny and allometric scaling. Twenty-five pediatric AUCRs were predicted from adult AUCR data. Predictive performance was evaluated by comparing predicted AUCR_pediatric values with observed values, using a 50-200% acceptability range. <b>Results</b>: Approach C demonstrated superior predictive capability, with only one out of 25 predictions falling outside the acceptability range. In contrast, both approaches A and B resulted in three values each outside this range. Further visual exploration and detailed performance analyses confirmed the enhanced accuracy of approach C in predicting pediatric DDIs compared with the other approaches. <b>Conclusions</b>: This study demonstrates that the proposed approach of considering both ontogeny and allometric scaling represents a robust and reasonable method to anticipate the extent of pediatric CYP-based DDIs when adult PK data are available.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"19 4","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13119140/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147819825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of <i>Chaenomeles japonica</i> Fruit Juice on Energy Balance and Biochemical and Histological Parameters in a Model of Diet-Induced Metabolic Syndrome in Rats.","authors":"Klementina Moneva-Marinova, Silvia Gancheva, Miroslav Eftimov, Maria Tzaneva, Milena Todorova, Mehmed Reyzov, Elis Rafailova, Maria Zhelyazkova-Savova, Stefka Valcheva-Kuzmanova","doi":"10.3390/ph19040609","DOIUrl":"10.3390/ph19040609","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Metabolic syndrome (MS) is associated with an increased cardiovascular risk. The aim of this study was to reveal the effects of <i>Chaenomeles japonica</i> fruit juice (CJFJ) on energy balance and biochemical and histological parameters in rats with diet-induced MS. <b>Methods</b>: Fifty Wistar rats were allocated into five groups. For ten weeks, the Control group received a standard laboratory diet and tap water, while the other groups were given a high-fat high-fructose (HFHF) diet. The Control and MS groups were treated with distilled water, while the other three groups were treated with CJFJ at increasing doses. <b>Results</b>: Rats on an HFHF diet consumed less food and more liquids and had a higher caloric intake than the Control group. Among the CJFJ-treated animals, an increased food consumption, as well as an increased total caloric intake, and no difference in body weight gain were observed in comparison with the MS group. CJFJ did not affect glucose tolerance or the triglyceride and total cholesterol levels. CJFJ prevented an HFHF-induced decrease in superoxide dismutase and caused a decrease in thiobarbituric acid-reactive substances in serum. The medium CJFJ dose prevented an HFHF-induced increase in adipose tissue indices. Liver and adipose tissue histology revealed a protective effect of CJFJ. <b>Conclusions</b>: CJFJ may exert beneficial effects on visceral adiposity, oxidative status, and histopathological changes in the liver and adipose tissue in rats with diet-induced MS.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"19 4","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13118728/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147819813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bromelain and Curcumin Oral Supplementation for Refractory Inherited Retinal Dystrophy-Related Macular Oedema: Changes in Macular Thickness and Visual Acuity over 12 Months.","authors":"Mattia D'Andrea, Carmen Dell'Aquila, Lucilla Barbano, Feliciana Menna, Antonio Di Renzo, Gaspare Colacino, Marco Marenco, Roberto Dell'Omo, Vincenzo Parisi, Lucia Ziccardi","doi":"10.3390/ph19040602","DOIUrl":"10.3390/ph19040602","url":null,"abstract":"<p><p><b>Objectives</b>: To evaluate the long-term effects on retinal structure and visual function of oral bromelain and curcumin supplementation in patients with inherited retinal dystrophies (IRD) complicated by persistent cystoid macular oedema (CMO). <b>Methods</b>: We retrospectively studied 20 eyes with genetically confirmed IRD complicated by CMO, with refractory to systemic or local treatments performed for 6 months. We collected baseline (V1) and follow-up (V2) data from these IRD-CMO patients, who were continuously supplemented with oral bromelain and curcumin for 12 months. Outcome measures were the Snellen best-corrected visual acuity (BCVA) and central macular thickness (CMT) values, collected by spectral-domain optical coherence tomography (OCT). Based on OCT scans, we classified IRD-CMO as microcystic or macrocystic, performing this sub-grouping in two eye cohorts (<i>n</i> = 10). Baseline median BCVA and CMT differences in both groups were verified (Mann-Whitney test). For both CMO groups, changes from V1 to V2 in median BCVA and CMT values were evaluated (Friedman test). <b>Results</b>: At baseline, both the median BCVA and CMT values were significantly different in both groups (<i>p</i> < 0.01 and <i>p</i> < 0.001). Between V1 and V2, in the microcystic CMO group, a slightly improved median BCVA was found, whereas the median CMT was reduced; however, this did not reach statistical significance (<i>p</i> = 0.6 and <i>p</i> = 0.2, respectively). In the macrocystic CMO group, a significant stable median BCVA was found from V1 to V2, with concomitant significant reduction in median CMT (<i>p</i> < 0.05 for both comparisons). <b>Conclusions</b>: Retinal structural improvement and visual function preservation were observed after oral bromelain and curcumin supplementation in macrocystic IRD-CMO. It is likely that the vasogenic component in macrocystic CMO is more responsive to nutraceutical molecules than the degenerative microcystic component.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"19 4","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13119060/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147819541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sodium Rutin Ameliorates Non-Alcoholic Fatty Liver Disease and Alleviates Insulin Resistance by Promoting Lipophagy.","authors":"Xue Zhang, Shuoshuo Li, Ping Zhang, Chenggang Zhang, Zengqiang Yuan","doi":"10.3390/ph19040604","DOIUrl":"10.3390/ph19040604","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Non-alcoholic fatty liver disease (NAFLD) is a prevalent metabolic disorder for which there are limited pharmacotherapies. Sodium rutin (NaR), a soluble flavonoid derivative, has shown beneficial metabolic effects, but its role in NAFLD remains unclear. This study investigates whether NaR ameliorates high-fat diet (HFD)-induced NAFLD and insulin resistance through promoting hepatic lipophagy. <b>Methods</b>: Male mice aged 8 weeks old were fed a HFD for 12 weeks with/without NaR supplementation. Body weight was measured every week. After 12 weeks of treatment, GTT and ITT were performed to assess insulin resistance. Then, the tissues were collected and hepatic histology, serum biochemistry, and markers of autophagy and senescence were assessed. <b>Results</b>: NaR treatment significantly attenuated HFD-induced weight gain, reduced visceral fat and liver weights, and ameliorated hepatic steatosis and vacuolization. NaR improved serum lipid profiles; lowered alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels; and reduced hepatic cellular senescence. NaR enhanced hepatic autophagy, evidenced by decreased p62 levels, increased LC3-II/LC3-I ratio, and enhanced colocalization of lipid droplets with LC3 and LAMP1 in vivo and in vitro. These changes were accompanied by improved glucose tolerance and insulin sensitivity. <b>Conclusions</b>: NaR effectively alleviates HFD-induced NAFLD and insulin resistance by activating hepatic lipophagy. These findings support NaR as a promising multi-targeted therapeutic candidate for NAFLD.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"19 4","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13118290/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147819715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evidence-Based Management of MASLD: GRADE Evaluation of Pharmacological Therapies.","authors":"Eleni A Karavia, Andreas Pittaras, Ourania Andreopoulou, Aikaterini Hatziri, Amalia Makrydimitri, Dimitrios Anagnostopoulos, Patroklos Vareltzis, Kyriakos E Kypreos","doi":"10.3390/ph19040605","DOIUrl":"10.3390/ph19040605","url":null,"abstract":"<p><p><b>Background/Objectives:</b> Non-alcoholic fatty liver disease (NAFLD), recently redefined as metabolic dysfunction-associated steatotic liver disease (MASLD), represents a growing global health burden closely linked to obesity, insulin resistance, and dietary patterns. Despite intense drug-development efforts, effective and widely approved pharmacological therapies remain limited. <b>Methods:</b> In this work, we systematically evaluated the quality of clinical evidence supporting currently proposed pharmacological treatments for MASLD/MASLD using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework, focusing on phase III and IV clinical trials. <b>Results:</b> Our analysis demonstrates that overall quality of evidence for most pharmacological agents ranges from very low to moderate, primarily due to imprecision and suspected publication bias. <b>Conclusions:</b> Overall, our findings reinforce that, in the current therapeutic landscape, pharmacological therapies should be reserved for carefully selected patients and interpreted in the context of limited evidence certainty.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"19 4","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13119189/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147819567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polysaccharides and Glycosides from <i>Aralia echinocaulis</i> Modulate Succinate Levels in the Gut to Target Intestinal Dendritic Cells via the Receptor GPR91 in the Treatment of Rheumatoid Arthritis.","authors":"Mengqiang Gao, Shanshan Ma, Yunzhi Li","doi":"10.3390/ph19040606","DOIUrl":"10.3390/ph19040606","url":null,"abstract":"<p><p><b>Background</b>: <i>Aralia echinocaulis</i> has therapeutic effects on rheumatoid arthritis (RA), with total polysaccharide and glycoside (TPGs) as main active components. RA pathogenesis involves gut microbiota dysbiosis and immune-metabolic crosstalk, but the role of microbiota-derived succinate in RA remains unclear. <b>Objective</b>: This study explored the role of succinate-GPR91 signaling in intestinal dendritic cells (DCs) in the context of RA and the therapeutic mechanism of <i>A. echinocaulis</i> TPGs. <b>Methods</b>: Collagen-induced arthritis (CIA) mice were treated with TPGs or exogenous succinate. Paw edema, inflammation, gut succinate levels, the Th17/regulatory T (Treg) balance, and DC activation via succinate-GPR91 were detected, and GPR91-targeting siRNA and CD4+ T-cell coculture assays for verification. <b>Results</b>: TPGs alleviated symptoms in CIA mice and restored the Th17/Treg balance by reducing intestinal succinate levels. Succinate activated DCs via GPR91 to promote Th17 differentiation, while TPGs suppressed DC maturation and Th17-driven inflammation, supporting the involvement of a gut-centric immunometabolic axis in RA. <b>Conclusions</b>: TPGs ameliorate RA by targeting the succinate-GPR91-Th17 pathway, identifying succinate as a novel RA target and TPGs as a potential microbiota-modulating agent.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"19 4","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13119086/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147819684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Resveratrol Induces Proteasomal Degradation of PTPN1 to Enhance Cisplatin Sensitivity in Epstein-Barr Virus-Associated Malignancies.","authors":"Na Liu, Yueshuo Li, Min Tang, Ya Cao, Li Shang, Feng Shi","doi":"10.3390/ph19040603","DOIUrl":"10.3390/ph19040603","url":null,"abstract":"<p><p><b>Background/Objectives</b>: EBV is an oncogenic virus linked to NPC and GC, driving cisplatin resistance. Resveratrol has anticancer activity, but its targets and mechanisms against EBV-positive cancers remain unclear. <b>Methods</b>: We assessed resveratrol's cytotoxicity in EBV-positive cells via functional assays, identified targets by chemical similarity search and molecular docking, and validated PTPN1 via in vitro experiments and nude mouse xenograft models. <b>Results</b>: Resveratrol inhibited EBV-positive cell viability in a time- and concentration- dependent manner, with IC50 values ranging from 35.85 to 145.7 μM across different cell lines at 24-72 h. Apoptosis rates increased by approximately 2- to 4-fold after 80 μM resveratrol treatment for 24 h. Resveratrol directly targeted PTPN1 (docking score = -4.89) and promoted its degradation via the proteasome pathway, as MG132 reversed this effect. Notably, resveratrol synergized with cisplatin (combination index < 1) to reverse cisplatin resistance in both in vitro and in vivo models. Furthermore, resveratrol induced EBV lytic reactivation through ROS production, as evidenced by the increased expression of BZLF1, BMRF1, and BALF2, which was attenuated by the ROS scavenger NAC. <b>Conclusions</b>: Our findings identify PTPN1 as a direct anticancer target of resveratrol in EBV-positive cancers. Resveratrol enhances the therapeutic efficacy of cisplatin via PTPN1 proteasomal degradation and induces EBV lytic reactivation through ROS accumulation. These findings provide a mechanistic basis for the development of novel combination therapies targeting EBV-associated malignancies.</p>","PeriodicalId":20198,"journal":{"name":"Pharmaceuticals","volume":"19 4","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13118724/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147819723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}