Phytotherapy Research最新文献

{"title":"Atractylenolide I Alleviates Lipotoxicity in Hepatocytes and Protects NAFLD in Mice Through SIRT1-Dependent IRE1α-XBP1 Pathway.","authors":"Hui Zhuge, Kaixin Chang, Shuzhen Sun, Qinchao Ding, Shanglei Lai, Xiaobing Dou, Qing Song, Songtao Li","doi":"10.1002/ptr.70406","DOIUrl":"10.1002/ptr.70406","url":null,"abstract":"<p><p>Atractylenolide I (AO-I), a major pharmacological ingredient derived from Atractylodes macrocephala, has been reported to possess multiple bioactivities. This study aimed to investigate the potential protective effects of AO-I against lipotoxicity in both cultured hepatocytes and mice with non-alcoholic fatty liver disease (NAFLD). The NAFLD model was established by feeding C57BL/6 mice a high-fat diet (HFD) for 12 weeks. Oral administration of AO-I at doses of 20 or 50 mg/kg body weight per day was explored. Lipotoxicity in AML12 hepatocytes was induced by incubation with palmitate for in vitro investigations on the roles of AO-I. The results demonstrated that supplementation with AO-I improved alanine transaminase (ALT), aspartate transaminase (AST), and liver histology in NAFLD mice. Furthermore, AO-I directly alleviated palmitate-induced lipotoxicity by reducing hepatocyte death. Mechanistic studies revealed that AO-I significantly attenuated lipotoxicity through its potential resistance to endoplasmic reticulum (ER) stress and IRE1α-XBP1 splicing both in vivo and in vitro. We identified that AO-I substantially rescued HFD- and palmitate-induced SIRT1 decline in mouse livers and hepatocytes, respectively, thereby improving liver injury and hepatocyte cell death. Mechanistic studies demonstrated that the amelioration of ER stress and lipotoxicity by AO-I supplementation depended on SIRT1 activity. Moreover, AO-I also mitigated IRE1α activation-triggered JNK/p38 MAPK hyperphosphorylation. In conclusion, our findings suggest that AO-I exhibits significant therapeutic effects for improving lipotoxicity in the liver and may be considered as a candidate for NAFLD therapy.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":"5758-5771"},"PeriodicalIF":8.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148397316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanistic Evaluation of Luteolin in Wound Healing of Diabetic Foot Ulcer via Nrf2 Signaling.","authors":"Muhammed Yusuf, Ayfer Busra Benkli, Ramiz Yusuf","doi":"10.1002/ptr.70425","DOIUrl":"10.1002/ptr.70425","url":null,"abstract":"<p><p>Diabetic foot ulcers (DFUs) are a leading cause of lower-limb amputation, with oxidative stress and ferroptosis playing critical roles in impaired wound healing. This study aimed to evaluate the therapeutic potential of luteolin (LU), a naturally occurring plant-derived flavonoid, in DFU repair and to elucidate its underlying molecular mechanisms. A DFU rat model was established using a high-fat/high-glucose diet combined with streptozotocin injection, followed by full-thickness skin wounding. LU was topically administered at different concentrations. Wound closure was monitored macroscopically, while histopathological changes, inflammatory cytokines, and growth factor levels were assessed by microscopy and ELISA. Network pharmacology and molecular docking analyses were performed to identify potential targets and signaling pathways, which were subsequently validated in vitro using human umbilical vein endothelial cells (HUVECs). LU significantly accelerated wound closure in a dose-dependent manner, accompanied by reduced oxidative stress and pro-inflammatory cytokine production, enhanced collagen deposition, increased angiogenesis, and upregulated expression of key growth factors. Bioinformatics analysis identified ferroptosis inhibition and activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway as central mechanisms, which were confirmed experimentally. LU reduced intracellular reactive oxygen species levels and lipid peroxidation and promoted HUVEC migration and viability. Notably, pharmacological inhibition of Nrf2 with ML385 markedly reversed the protective effects of LU, indicating a pivotal role for Nrf2 signaling. Collectively, these findings demonstrate that LU promotes DFU healing through activation of Nrf2 signaling and suppression of ferroptosis, supporting its potential as a therapeutic candidate for the management of diabetic wounds.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":"5901-5917"},"PeriodicalIF":8.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13636140/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148685529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential of Ginkgo biloba Extract to Intervene in Chronic Inflammation-Related Diseases.","authors":"Yipeng Lin, Inho Cho, Xue Zhu, Ke Wang, Ling Zhu, Wenchang Wong, Michael Murray, Fanfan Zhou","doi":"10.1002/ptr.70467","DOIUrl":"https://doi.org/10.1002/ptr.70467","url":null,"abstract":"<p><p>Chronic inflammation is a pathological mechanism of central importance that underpins a wide range of diseases, including neurodegenerative, cardiovascular, respiratory, gastrointestinal, and dermatological disorders. Ginkgo biloba extract (GBE), a standardized formulation derived from Ginkgo biloba leaves, has attracted growing attention due to its anti-inflammatory, antioxidant, and neuroprotective properties. This review comprehensively summarizes the current preclinical and clinical evidence regarding the therapeutic potential of GBE and its active constituents in inflammation-related diseases. GBE has been shown to attenuate pro-inflammatory cytokine production, suppress nuclear factor kappa B (NF-κB) activation, restore redox homeostasis, and modulate disease-relevant pathways in models of Alzheimer's disease, Parkinson's disease, multiple sclerosis, atherosclerosis, asthma, chronic obstructive pulmonary disease, inflammatory bowel disease, inflammatory skin conditions and rheumatoid arthritis. While these findings highlight the promising multi-targeted anti-inflammatory actions of GBE, limitations remain regarding the identification of specific active compounds, standardization of formulations, and the availability of robust clinical evidence. Further research is warranted to clarify the mechanisms of action and optimize delivery of GBE, and to validate the efficacy and safety of GBE in large-scale clinical trials.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149113601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of Green Tea Supplementation on Chemoprevention at Different Stages of Carcinogenesis: A Systematic Review.","authors":"Thaís Moreira Machado, Mariene Garcia Gomes, Érika Yuri Hirose Murahara, Ana Lúcia Chalhoub Chediac Rodrigues, Ariane Nadolskis Severine, Thais Giovaninni Roberto, Sinara Laurini Rossato","doi":"10.1002/ptr.70451","DOIUrl":"https://doi.org/10.1002/ptr.70451","url":null,"abstract":"<p><p>Green tea catechins have chemopreventive potential; however, the clinical evidence remains inconsistent. This review evaluated the effects of supplementation with green tea derivatives on chemoprevention at different stages of carcinogenesis. PubMed, Embase, Web of Science, Scopus, the Cochrane Library, CINAHL, and Google Scholar were searched for randomised and non-randomised clinical trials in adults. Random-effects meta-analyses were used to estimate relative risks (RRs) and 95% confidence intervals (95% CIs). Risk of bias and certainty of the evidence were assessed using RoB 2, ROBINS-I, and GRADE. Of the 7089 records identified, 19 studies, comprising a total of 3121 participants, were included. Nine studies were included in the meta-analyses. No statistically significant associations were observed for regression of cervical lesions (RR = 2.40; 95% CI: 0.36-16.23), HPV clearance (RR = 1.19; 95% CI: 0.68-2.07), prostate cancer incidence (RR = 0.52; 95% CI: 0.22-1.23), or colorectal adenoma recurrence (RR = 0.71; 95% CI: 0.50-1.00). The qualitative synthesis showed heterogeneous findings, including favourable effects on some biomarkers. The certainty of the evidence was rated as low or very low. Although no association was observed between green tea supplementation and the outcomes evaluated in the meta-analyses, the findings should be interpreted with caution because of methodological heterogeneity, risk of bias, and the low or very low certainty of the evidence. Clinical trials with larger sample sizes and populations that are more comparable in terms of the type and stage of carcinogenesis are needed to clarify the chemopreventive potential of green tea supplementation.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149113574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Natural Products Exhibit Therapeutic Potential in Treating Rheumatoid Arthritis by Targeting the PI3K/Akt Signaling Pathway.","authors":"Haishuo Ren, Yige Wang, Wenjing Ma, Omachi Daniel Ogaji, Shujing Chen, Kunze Du, Xuemi Zhang, Bo Xu, Shanxing Zhai, Shiming Fang, Yanxu Chang","doi":"10.1002/ptr.70454","DOIUrl":"https://doi.org/10.1002/ptr.70454","url":null,"abstract":"<p><p>Rheumatoid arthritis (RA) is a persistent, systemic autoimmune disorder that primarily affects the joints. The progression of RA is driven by the activation of various intracellular signaling pathways, among which the PI3K/Akt signaling pathway regulates crucial biological processes associated with RA. According to reports, GSK3, Bcl-2, FOXOs, p53, mTOR, and NF-κB, the downstream targets of PI3K/Akt, are closely related to the pathological process of synovial inflammation, hyperplasia, angiogenesis, and bone destruction in RA. In recent years, many natural products, primarily flavonoids, terpenoids, alkaloids, and polyphenols, have been found to play a role in treating RA through the PI3K/Akt pathway. Unlike conventional treatments, natural products exert multi-target effects and possess structural diversity, making them valuable sources for drug discovery. Therefore, we summarized the studies on treatment of RA through the PI3K/Akt signaling pathway, suggesting that natural monomeric compounds, herbal extracts, and traditional drug prescriptions modulating the downstream targets of the PI3K/Akt pathway, mainly mTOR, Bcl-2, and NF-κB, are promising strategies for RA treatment. This review was conducted with the aim of providing a scientific foundation and methods for the treatment of RA.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149113518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oxypaeoniflorin Attenuates Alcohol-Associated Liver Disease, Potentially Involving TEAD4-Mediated Inflammatory Signaling Cascades.","authors":"Jiang-Tao Zhong, Hao Yue, Ze-Hao Wang, Ming Liu, Hai-Ming Sun, Jian Song","doi":"10.1002/ptr.70465","DOIUrl":"https://doi.org/10.1002/ptr.70465","url":null,"abstract":"<p><p>This study investigates the hepatoprotective effects and underlying molecular mechanisms of Oxypaeoniflorin (Opae) against alcohol-associated liver disease (ALD). An in vivo ALD mouse model was established by chronic feeding of Lieber-DeCarli EtOH-containing liquid diets combined with TEAD4 silencing is utilized to explore the protective function of Opae. Opae treatment effectively ameliorated alcoholic liver damage, accompanied by significant downregulation of hepatic P-YAP1, TEAD1, and TEAD4 levels, as well as reduced expression of the pyroptosis-associated proteins NLRP3 and IL-1β. RNA sequencing analysis further identified the NOD-like receptor/mitophagy/Hippo signaling axis as the core regulatory network mediating Opae-induced hepatoprotection. Mechanistically, dual-luciferase reporter assays in AML-12 hepatocytes validated the direct binding of TEAD4 to the NLRP3 promoter. Both siRNA-mediated TEAD4 silencing in AML-12 cells and shRNA-mediated hepatic TEAD4 silencing in mice markedly suppressed NLRP3 expression and alleviated liver inflammatory responses. Notably, TEAD4 depletion abrogated EtOH-induced NLRP3 activation, confirming the essential transcriptional regulatory role of TEAD4 on NLRP3. In addition to the intrinsic regulatory effect on hepatocytes, Opae inhibits pyroptosis in LPS-stimulated mouse peritoneal macrophages (MPMs). Conditioned medium collected from Opae-treated MPMs significantly attenuated EtOH-induced inflammatory injury in primary mouse hepatocytes. Collectively, Opae exerts prominent hepatoprotective effects in ALD by suppressing TEAD4-NLRP3-mediated pyroptosis.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149081290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulating Lipid Metabolism in Cancer: The Therapeutic Potential of Traditional Chinese Medicine.","authors":"Yufeng Gao, Huiming Huang, Xuejiao Wei, Xiaoxue Wang, Wanying Xie, Xinyu Qiu, Fei Wang, Zhuguo Wang, Ruoxin Zhang, Yilin Cai, Changhai Qu, Zhongdong Hu","doi":"10.1002/ptr.70461","DOIUrl":"https://doi.org/10.1002/ptr.70461","url":null,"abstract":"<p><p>Lipid metabolic reprogramming is a key feature of tumor cells to adapt to the microenvironment and plays an important role in tumor growth, invasion, and metastasis. This article provides a systematic review of the pathological mechanisms underlying lipid metabolism disorders in tumor cells, including abnormalities in fatty acid (FA) and cholesterol metabolism and their association with tumor progression. Furthermore, it summarizes the mechanisms by which traditional Chinese medicine (TCM) and its natural active compounds regulate lipid metabolism through multiple targets and pathways, such as inhibiting FA uptake and synthesis and modulating cholesterol metabolism. Existing studies have demonstrated that targeted regulation of lipid metabolism by TCM offers a novel strategy for antitumor therapy. This approach holds the potential to reduce toxicity and enhance efficacy, providing new insights into the treatment of metabolic disorder-related tumors.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149063694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of Active Compounds of Centipeda minima for Potentiating Tumor Immunotherapy in Non-Small Cell Lung Cancer via FANCD2-cGAS/STING/IFN-I Signaling Axis.","authors":"Han-Chen Wang, Chu-Ying Chen, Jiang-Tao Xiao, Rou-Qiao Zheng, Wen-Da He, Zi-Wei Xu, Su-Fen Wei, Tao Su, Guang-Biao Zhou, Yong-Qiang Liu","doi":"10.1002/ptr.70460","DOIUrl":"https://doi.org/10.1002/ptr.70460","url":null,"abstract":"<p><p>Activation of cGAS/STING/IFN-I signaling pathway serves as a potential therapeutic strategy to enhance CD8⁺ T cells infiltration and augment antitumor immunotherapy. The medicinal herb Centipeda minima has been traditionally employed to treat respiratory diseases and cancer; however, whether C. minima and its bioactive constituents can activate CD8⁺ T cell-mediated antitumor immunity in non-small cell lung cancer (NSCLC) remains elusive. In this study, the ethanol extract of C. minima (ECM) significantly enhanced the cytotoxic activity of human peripheral blood mononuclear cell-derived activated T cells and murine primary CD8⁺ T cells against NSCLC cells, and promoted CD8⁺ T cell infiltration in the LLC syngeneic tumor model. RNA-seq profiling indicated that ECM potentially triggers type-I interferon (IFN-I)-mediated innate immunity in NSCLC. Mechanistically, ECM treatment activated the cGAS/STING pathway in NSCLC cells, as evidenced by increased phosphorylation of TBK1 and IRF3, elevated IFN-I gene expression, and enhanced CD8⁺ T cells activity. Notably, ECM markedly downregulated both mitochondrial and nuclear FANCD2 protein levels, which may facilitate cytosolic release of mitochondrial and nuclear DNA, thereby stimulating the cGAS/STING/IFN-I signaling axis. ECM-induced FANCD2 downregulation was markedly reversed by the proteasome inhibitor MG-132. Combination treatment with ECM and anti-PD-1 antibody synergistically suppressed tumor growth in the LLC syngeneic model, accompanied by elevated IFN-I expression and pronounced recruitment of activated CD8⁺ T cells. Moreover, 3-O-methylquercetin and several sesquiterpene lactones abundant in ECM were identified to downregulate FANCD2, activate TBK1/IRF3 pathway, and enhance IFN-I expression in NSCLC cells. Among these active compounds, arnicolide D promoted FANCD2 degradation in a proteasome-dependent manner, whereas 3-O-methylquercetin predominantly suppressed FANCD2 gene expression. Collectively, our findings suggest that FANCD2 may serve as a novel therapeutic target for enhancing antitumor innate immunity, and that C. minima along with its active compounds can potentiate antitumor immunotherapy by activating the FANCD2-cGAS/STING/IFN-I signaling axis.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149040214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ginsenoside Rh1 Attenuates Alzheimer's Disease-Like Deficits by Modulating Oxidative Stress and Mitochondrial Dysfunction via SIRT1-Related Signaling.","authors":"Shi-Lu Li, Tao Lin, Wan-Chen Zou, Ya-Jun Wang, Jing-Tian Zhang, Zi Wang, Hong-Yuan Li, Long Chen, Li-Chun Zhao, Shen Ren, Wei Li","doi":"10.1002/ptr.70459","DOIUrl":"https://doi.org/10.1002/ptr.70459","url":null,"abstract":"<p><p>Alzheimer's disease (AD) remains a progressive neurodegenerative disorder with limited therapeutic options. Ginsenoside Rh1 has been reported to possess neuroprotective properties, yet its specific role and underlying mechanisms in AD are not fully understood. This study aimed to investigate the protective effects of Rh1 against AD-related deficits and elucidate its molecular mechanisms. Using a D-galactose and AlCl₃-induced AD-like mouse model and an okadaic acid (OA)-injured HT22 hippocampal neuronal cell model, we demonstrated that Rh1 administration significantly ameliorated spatial learning and memory impairments, reduced hippocampal neuronal damage, and suppressed abnormal Tau hyperphosphorylation. Serum metabolomics analysis revealed that Rh1 markedly modulated amino acid metabolism pathways in AD-like mice, notably increasing aspartate (Asp) levels and decreasing glutamate (Glu) levels. Mechanistically, Rh1 activated the Nrf2 antioxidant pathway, thereby alleviating cellular oxidative stress. Concurrently, Rh1 ameliorated mitochondrial dysfunction by enhancing mitochondrial biogenesis, improving the mitochondrial fusion-fission balance, and modulating mitophagy. Importantly, the SIRT1 inhibitor EX-527 and SIRT1 knockdown both significantly reversed these protective effects. Cellular thermal shift assay and molecular docking suggested a potential interaction between Rh1 and SIRT1. In conclusion, our findings indicate that ginsenoside Rh1 exerts neuroprotective effects against AD in vivo and in vitro, at least partly through SIRT1-related signaling, which subsequently attenuates oxidative stress and ameliorates mitochondrial dysfunction. These results suggest that Rh1 may represent a promising candidate for further investigation for AD intervention.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149040226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neohesperidin Alleviates Ferroptosis in Doxorubicin-Induced Cardiotoxicity via Mettl3-m⁶A-Nrf2 Signaling.","authors":"Ruijia Wen, Xin Dong, Haowen Zhuang, Yusheng Huang, Mengyuan Wang, Zhongzheng Zhang, Jinhong Chen, Wei Wang, Chun Li, Junyan Wang","doi":"10.1002/ptr.70458","DOIUrl":"https://doi.org/10.1002/ptr.70458","url":null,"abstract":"<p><p>Doxorubicin (DOX) has antitumor efficacy, but its clinical application is restricted by multiple side effects, especially cardiotoxicity. Neohesperidin, a flavonoid in citrus fruits, has various health benefits. The aim of this study was to explore the cardioprotective effects and mechanisms of neohesperidin against DOX-induced cardiotoxicity (DIC). The study used DOX-treated mice to evaluate cardiac function and cardiomyocyte injury. In addition, primary cardiomyocytes treated with DOX were used to measure cell viability and death. FIN56, a ferroptosis inhibitor, was used to test the relationship between neohesperidin's beneficial effect and ferroptosis. Mechanistic investigations were carried out to explore the role of N6-methyladenosine (m⁶A) levels, nuclear factor erythroid-2-related factor 2 (Nrf2) expression, and Methyltransferase-like 3 (Mettl3) in the cardioprotective effect of neohesperidin. Overexpression and knockdown of Mettl3 were also performed to confirm its role in the cardioprotective effect. Neohesperidin attenuated cardiac function and cardiomyocyte injury in DOX-treated mice. It alleviated DOX-induced oxidative stress by reducing reactive oxygen species and malondialdehyde levels and increasing superoxide dismutase and glutathione levels, restoring ATP production. In DOX-treated primary cardiomyocytes, neohesperidin increased cell viability and decreased cell death. FIN56 abolished the beneficial effect of neohesperidin. Mechanistically, neohesperidin decreased m⁶A levels, leading to increased Nrf2 expression. Nrf2 activation was related to the inhibition of Mettl3, an m⁶A \"writer,\" which protected cardiomyocytes against DOX-induced ferroptosis. Overexpressing Mettl3 reversed the cardioprotective effects of neohesperidin and diminished its benefits on ferroptosis. These findings suggest that neohesperidin exerts a cardioprotective effect against DIC by inhibiting ferroptosis. This effect is achieved by regulating the Mettl3-m⁶A-Nrf2 signaling pathway, indicating the therapeutic potential of neohesperidin.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149031098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}