Phytotherapy Research最新文献

{"title":"Luteoloside Inhibits the Progression and Enhances Chemosensitivity to Cytarabine in Acute Myeloid Leukemia via β-Catenin/c-Myc Axis.","authors":"Xiaofang Wang, Fan Zhao, Yangya Pan, Fanfan Li, Jiaqian Pan, Xinyi Zhang, Ye Yang, Songfu Jiang, Shenghui Zhang, Kang Yu, Yixiang Han","doi":"10.1002/ptr.70416","DOIUrl":"10.1002/ptr.70416","url":null,"abstract":"<p><p>Acute myeloid leukemia (AML) is one of the most common and lethal hematologic malignancies with limited possibilities for treatment. Thus, more effective therapeutic drugs are imperatively needed to fulfill current unmet medical requirements. Luteoloside, derived from the traditional Chinese medicine Lonicera japonica , demonstrates potent anti-tumor activity against solid tumors, but its effects and mechanisms in hematologic malignancies like AML remain unclear. Herein, we found that luteoloside dramatically impaired the proliferation and clonogenic capacity of AML cells and induced cell cycle arrest and reduced the cells at S phase. Furthermore, luteoloside induced apoptosis and promoted differentiation of these cells. Mechanism analysis revealed that luteoloside attenuated β-catenin in the nucleus, thereby reducing the expression of its downstream effector c-Myc. Activation of Wnt/β-catenin signaling by a GSK-3β inhibitor LiCl reversed the inhibitory effect of luteoloside on AML cell proliferation, apoptosis, and differentiation. Luteoloside significantly reduced the transplantation rate of primary AML cells in a patient-derived xenografts (PDX) model. Combined treatment with luteoloside and cytarabine (Ara-C) showed a synergistic anti-AML effect in vitro, and markedly reduced leukemia burden and prolonged the survival in the orthotopic C1498 murine AML model. Collectively, our findings demonstrate that luteoloside suppresses AML cell proliferation, induces apoptosis and differentiation by targeting the β-catenin/c-Myc axis, and exhibits synergistic effects with Ara-C. These results underscore its potential as a promising adjunctive therapy for AML.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":"5772-5786"},"PeriodicalIF":8.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148412319","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":"Allium cepa And Its-Associated Phytochemicals: Evidence From in Vitro, in Vivo, and Human Studies on Antioxidant Effects.","authors":"Mohammad Salar Boustani, Mohammad Hossein Eshaghi Ghalibaf, Sima Beigoli, Narges Ghadimi, Seyed Mohammad Sajjadi, Pejman Hosseinzadeh, Mahdie Delshad, Mohammad Hossein Boskabady","doi":"10.1002/ptr.70413","DOIUrl":"10.1002/ptr.70413","url":null,"abstract":"<p><p>Various pharmacological properties and therapeutic effects were shown for Allium cepa L. (Liliaceae), ( A. cepa ) or onion and its derivatives including their effects on oxidative stress in different conditions. In this article, an update and comprehensive review of antioxidant effects of A. cepa and A. cepa -associated phytochemicals as well as the underlying molecular mechanisms are provided. The literature on antioxidant effects of A. cepa published between 2015 and the end of July 2025 was searched on database like PubMed, WOS, Science direct and Scopus. A. cepa and its constituents showed antioxidant in various conditions such as cardiovascular, endocrine and metabolic, gastrointestinal and liver, immunological, hematological and autoimmune, urogenital, neurologic and respiratory disorders as well as cancer and neoplasia. The antioxidant effects of A. cepa and its derivatives were achieved by decreasing lipid peroxidation (LPO), malondialdehyde (MDA), nitric oxide (NO), and endothelial nitric oxide synthase (eNOS), inhibiting NADPH oxidase (NOX) activity but enhancing antioxidants such as superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), glutathione peroxidase (GSH-Px), glutathione peroxidase omega (GSPO), thioredoxin reductase (TrxR), glutathione-S-transferase (GST) and glutathione reductase (GR) activities and thiol levels. Therefore A. cepa and A. cepa -associated phytochemicals showed potent antioxidant effects indicating their possible therapeutic value for treatment of disorders associated with oxidative stress.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":"5853-5885"},"PeriodicalIF":8.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148674093","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":"Cordycepin Alleviates Non Alcoholic Fatty Liver Disease Progression by Stabilizing GCH1 to Inhibit Ferroptosis.","authors":"Chenyang Han, Jian Sheng, Hongyan Pei, Wenyan Li, Shasha Wu, Yi Yang, Chenxi Cao, Zhiling Tang","doi":"10.1002/ptr.70424","DOIUrl":"10.1002/ptr.70424","url":null,"abstract":"<p><p>To investigate the effects and targets of cordycepin (COR) in alleviating non-alcoholic fatty liver disease (NAFLD). High-fat diet was used to induce NAFLD in mice, and after COR gavage administration, changes in liver function, glucose and lipid metabolism, and ferroptosis-related signaling were detected. In vitro, palmitic acid (PA) and oleic acid (PSA) were combined to induce hepatocyte lipid injury. The effect of COR on hepatocyte ferroptosis was examined. GCH1 conditional knockout mice (GCH1-CKO) and hepatocyte models were constructed, and AAV9-GCH1 was used to construct GCH1 overexpression mouse models to verify the effect of GCH1 on NAFLD. CETSA-WB, co-immunoprecipitation, and DARTS were employed in the COR-GCH1 interaction and mechanism studies to validate the targeted binding relationship between COR and GCH1. Animal-level studies showed that COR could improve glucose and lipid metabolism and liver function damage in mouse NAFLD, inhibit ferroptosis occurrence and lipid peroxidation injury. Cell-level results showed that COR could inhibit hepatocyte ferroptosis. The ferroptosis-inhibiting effect of GCH1 is independent of GPX4 and other signals; GCH1 directly inhibits reactive oxygen free radicals and suppresses lipid metabolism peroxidation damage. COR's effects are not related to classical anti-ferroptosis signals such as GPX4 and Nrf2, but only related to GCH1. COR can target the GCH1 K155 site, stabilize protein levels by inhibiting GCH1 ubiquitination degradation, and when GCH1 is knocked out, COR's effects are antagonized. GCH1 has a protective role in NAFLD, and this effect is independent of classical GPX4 signaling. COR can target the GCH1 K155 site, inhibit GCH1 ubiquitination thereby preventing protein degradation and exerting protein stabilization. COR elevates GCH1 levels to inhibit ferroptosis. COR is a small molecule with potential for treating NAFLD.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":"5886-5900"},"PeriodicalIF":8.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13636126/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148679539","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":"Systematic Review and Meta-Analysis: Plant-Based Therapy for Irritable Bowel Syndrome.","authors":"Anselm Meyer, Jonas Auer, Lorena Cascant-Ortolano, Niclas Schreiber, Amy Zimmermann-Klemd, Carsten Gründemann, Philipp Busche, Jörg Schirra, Mark R Fox","doi":"10.1002/ptr.70421","DOIUrl":"10.1002/ptr.70421","url":null,"abstract":"<p><p>Irritable bowel syndrome (IBS) is a common disorder of brain-gut interaction that presents with abdominal pain, bloating associated with variable stool consistency. Many IBS patients prefer plant-based preparations to pharmacological therapy; however, the utility of this approach is not well established. To address this issue, a systematic review with meta-analysis to assess the efficacy and safety of plant-based therapy in IBS patients was performed. Literature search with 3 electronic databases (Medline via PubMed, Embase via Ovid, and Web of Science Core Collection) from inception to May 2024. Efficacy was assessed using dichotomous ratings of change in IBS symptoms. A random effects model with 95% confidence intervals was used. Through the screening process, 60 eligible studies were identified (6329 patients). Meta-analysis was performed for fiber (8 studies, RR = 1.22; 95% CI: 1.00-1.49), peppermint oil (7 studies, RR = 1.63; 95% CI: 1.33-2.00), Aloe vera (3 studies, RR = 1.25; 95% CI: 0.76-2.06), and Chinese herbal medicine (7 studies, RR = 1.56; 95% CI: 1.27-1.92). For other plant-based substances investigated in at least one randomized controlled trial (RCT) (e.g., St. John's wort, Anise oil), there were insufficient data for a meta-analysis. The quality of many studies was limited. The findings demonstrate that the treatment of IBS patients with peppermint oil and Chinese herbal medicine were more effective than placebo and had a good safety profile. Dietary fiber showed effects that approached significance. Further, well-powered RCTs are needed to establish the place of plant-based preparations in IBS treatment.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":"5918-5950"},"PeriodicalIF":8.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13636137/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148701975","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":"Lycium barbarum Leaf Flavonoids Exert Anti-Aging Effects by Regulating the Keap1-Nrf2-HO-1 and Cell Adhesion Molecule Signaling Pathways.","authors":"Jinwang Liu, Xue Yang, Xiaotong Zha, Jiangxue Qin, Jing Ren, Aihua Hao, Xuemei Meng, Yanli Fan, Yuan Liu","doi":"10.1002/ptr.70390","DOIUrl":"10.1002/ptr.70390","url":null,"abstract":"<p><p>Aging significantly increases susceptibility to chronic diseases, underscoring the need for effective interventions. Flavonoids from Lycium barbarum leaves (LBLF), which are notably more abundant in the leaves than in the berries, have demonstrated anti-aging properties. However, their underlying mechanisms remain unclear, thereby limiting their further development. To address this gap, the present study aims to systematically evaluate the anti-aging potential of LBLF using integrated in vitro and in vivo approaches. In the experimental procedure, LBLF was tested at concentrations ranging from 20 to 60 μg/mL in vitro and at doses of 50 to 120 mg/kg in vivo. For this purpose, hydrogen peroxide-stressed Human glioblastoma cell line T98G (T98G cells) and D-galactose-induced aging mice were employed as models, in which oxidative stress markers and cellular senescence indicators were assessed. Additionally, RNA-Seq analysis of hippocampal tissue was performed to identify key differentially expressed genes and related pathways. The results suggest that the anti-aging effects of LBLF may be associated with changes in oxidative stress-related and cell adhesion-related pathways. Specifically, LBLF downregulated Keap1 and upregulated Nrf2 and HO-1 in the Keap1-Nrf2/HO-1 pathway, while increasing antioxidant enzyme activity and reducing malondialdehyde levels (p < 0.05). Transcriptomic analysis identified 402 differentially expressed genes, with significant enrichment in the cell adhesion pathway (FDR < 0.05), including upregulation of Cdh1 (1.38-fold) and downregulation of Cldn1 (1.45-fold) (p < 0.05). In short, these results indicate that LBLF alleviates oxidative stress via the Keap1-Nrf2/HO-1 axis and modulates the cell adhesion pathway, collectively exerting anti-aging effects. In summary, this study preliminarily proposes potential molecular targets of LBLF and provides supporting evidence for the pharmacological application of LBLF.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":"5741-5757"},"PeriodicalIF":8.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148391520","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":"Therapeutic Properties and Underlying Mechanisms of Traditional Chinese Medicine in Managing Rheumatoid Arthritis: An Integrative Review of Clinical and Molecular Findings.","authors":"Jianting Wen, Jian Liu, Lei Wan, Fanfan Wang, Yang Li","doi":"10.1002/ptr.70429","DOIUrl":"10.1002/ptr.70429","url":null,"abstract":"<p><p>Traditional Chinese medicine (TCM) has a long-standing history in the treatment of rheumatoid arthritis (RA), known as \"Bi Zheng,\" and offers a comprehensive therapeutic approach characterized by multi-target and multi-pathway mechanisms. Modern pharmacological research has demonstrated that bioactive compounds and herbal formulas derived from TCM (e.g., triptolide [TPL] from Tripterygium wilfordii and the Xinfeng Capsule [XFC]) effectively interfere with the complex pathogenesis of RA. These interventions modulate diverse pathological processes, including the suppression of pro-inflammatory cytokines (e.g., TNF-α, IL-6, and IL-1β), induction of apoptosis in hyperplastic synovial cells, and regulation of novel cell death pathways (such as ferroptosis and pyroptosis). Furthermore, TCM components exhibit potent antioxidant properties, inhibit pathological angiogenesis, ameliorate hypercoagulable states, and restore gut microbiota dysbiosis, which is increasingly recognized as a key environmental factor in RA development. Notably, emerging evidence highlights the critical role of non-coding RNAs (ncRNAs) as mediators of these therapeutic effects. Concurrently, a growing body of clinical evidence from randomized controlled trials (RCTs), cohort studies, and real-world data mining consistently confirms the significant efficacy and safety of TCM interventions in relieving RA symptoms, improving joint function, and reducing disease activity. By integrating preclinical and clinical findings, a robust evidence chain emerges, validating traditional TCM concepts through modern scientific rigor. Therefore, TCM represents a valuable resource for RA drug discovery and integrative treatment strategies. Further in-depth investigation is needed into its specific molecular targets, optimal formulations, and long-term clinical outcomes to facilitate its global translation and application.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":"6005-6042"},"PeriodicalIF":8.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13636168/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148796622","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":"A Critical Review of Cytochrome P450 Enzyme Inhibition by Herbal Phytochemicals: Implications for Drug Interaction Prediction and Herbal Safety.","authors":"Yanping Li, Lanlan Gan, Yuanlin Wu, Yumeng Liu, Ni Zhang, Tingting Jiang, Jianhong Chen, Fang Liu, Dan Peng, Yao Liu","doi":"10.1002/ptr.70414","DOIUrl":"10.1002/ptr.70414","url":null,"abstract":"<p><p>Cytochrome P450 (CYP450) enzymes are the most important phase I drug-metabolizing enzymes in humans, and regulation of their activity is directly related to drug efficacy and safety. As herbal medicines gain worldwide popularity, their concurrent use with drugs has become more common. The effect of phytochemicals from herbal sources on CYP450 activity is a critical factor contributing to clinical drug interactions. When CYP450 activity is inhibited, it is easy to cause the accumulation of substrate drugs and cause toxic side effects, or the formation of toxic intermediates due to altered metabolic pathways, which seriously threaten the medication safety of patients. However, only a limited number of herbs have been evaluated for their impact on CYP450 enzyme activity, and data on the inhibitory effects of key CYP450 isoforms involved in drug metabolism remain scarce. Particularly noteworthy is the lack of research on the mechanisms of herb-drug interactions (HDIs) and the constituents of compound herbs, which impedes comprehensive identification and evaluation of potential clinical risks. This paper provides a systematic summary of CYP450 phytochemical inhibitors such as alkaloids, quinones, flavonoids, terpenoids, and coumarins in herbal medicine. In addition to the common CYP450 isoforms (e.g., CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4), this review also focuses on some less frequently studied isoforms, including CYP1B1, CYP7A1, CYP8B1, CYP17A1, and CYP19A1. Through an in-depth analysis of the current research limitations, this study proposes targeted directions for technological innovation and research standardization, thereby providing a scientific basis for addressing the research gap in HDIs and herb-herb interactions (HHIs) and formulating strategies for the rational use of herbs and standards for safety evaluation.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":"5672-5719"},"PeriodicalIF":8.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148376136","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":"Immunomodulatory Properties of Withania somnifera: Regulation of Innate Immune Cells and Clinical Implications.","authors":"Rana Yukta, Sonalika Gupta, Gagandeep Kaur, Partha Sarathi Mondal, Milirani Das, Anagha Ranade, Alok Kumar Srivastava, Sachin Kumar, Manoj Kumar Barthwal, Madhu Dikshit","doi":"10.1002/ptr.70427","DOIUrl":"10.1002/ptr.70427","url":null,"abstract":"<p><p>Withania somnifera (L.) Dunal (WS), commonly known as Ashwagandha, is a prominent medicinal herb in Ayurveda, with extensive therapeutic potential attributed to its diverse phytochemical profile. This review critically examines the immunomodulatory properties of WS, focusing on innate immune cell populations, including neutrophils, eosinophils, macrophages, dendritic cells, and natural killer (NK) cells. Bioactive constituents, particularly withanolides and withaferin A derived mainly from roots and leaves, orchestrate immune responses through modulation of cytokine networks, enhancement of phagocytic activity, and attenuation of oxidative stress. WS constituents regulate key signaling pathways, including ERK, NF-κB, and JAK/STAT, at transcriptional and translational levels. WS exhibits a dual immunoregulatory role by enhancing innate immune cell functionality while suppressing pathological inflammation in allergic and chronic inflammatory disorders. However, critical gaps persist in elucidating its molecular mechanisms, establishing phytochemical standardization, and defining context-specific dosing regimens. Collectively, current evidence positions WS as a promising candidate for the management of autoimmune, infectious, and inflammatory diseases. However, it further highlights the need for rigorous mechanistic studies and well-designed clinical trials to enable its integration into evidence-based therapeutics.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":"5951-5972"},"PeriodicalIF":8.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13636102/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148761156","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":"Targeting TIME With Phytochemicals: A Promising Approach Against Lung Cancer.","authors":"Feng Xiang, Liyue Lu, Fangfei Li, Yunnan Jing, Yanhua Li, Jie Cao, Caizhi Xiao, Jingyan Yang, Qinxiu Zhang, Jiangchuan Dong","doi":"10.1002/ptr.70381","DOIUrl":"10.1002/ptr.70381","url":null,"abstract":"<p><p>Lung cancer remains an aggressive and highly prevalent disease worldwide, causing an estimated 1.8 million deaths in 2022 and becoming a leading cause of cancer-related mortality. Resistance to current therapies necessitates novel approaches that target the tumour immune microenvironment (TIME), which is crucial for disease progression. Studies suggest that certain phytochemicals can enhance antitumour immunity by modulating the TIME. This systematic review aimed to elucidate and synthesise the mechanisms by which phytochemicals exert antitumour immunomodulatory effects in lung cancer and to assess their therapeutic potential and translational challenges. We comprehensively reviewed the literature from PubMed, Web of Science, and China National Knowledge Infrastructure (CNKI) until December 2025. Phytochemical mechanisms were analysed and classified based on their chemical structures and specific targets within the TIME. Phytochemicals effectively reprogrammed the immunosuppressive TIME using multi-target strategies. Key actions include the inhibition of immunosuppressive cells-such as myeloid-derived suppressor cells (MDSCs), Treg cells, and M2-polarised macrophages (e.g., via STAT3 downregulation by dihydroisotanshinone I)-activation of effector cells (e.g., NK cells, CD8+ T cells, and M1 macrophages), and the reversal of T helper cell drift (e.g., panaxan and aesculetin). This multipronged modulation offers superior efficacy by enhancing CD8+ T cell responses and overcoming functional exhaustion. This review validates the significant potential of phytochemicals as novel multi-target therapeutic agents for TIME-targeted therapy in lung cancer. Future research should prioritise addressing pharmacological challenges to accelerate rational clinical integration.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":"5805-5830"},"PeriodicalIF":8.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148437505","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":"Salvianolic Acid A Inhibits Ferroptosis in Endothelial Cells and the Progression of Atherosclerosis by Augmenting the Mitochondrial Homeostasis Pathway Associated With Adiponectin Receptor 1.","authors":"Ji Zhu, Jianan Guo, Jing Liu, Cheng Chen, Hang Chen, Cui Wang, Aini Yuan, Dezhao Lu, Yifei Le","doi":"10.1002/ptr.70419","DOIUrl":"10.1002/ptr.70419","url":null,"abstract":"<p><p>Endothelial cell ferroptosis drives atherosclerosis. Salvianolic acid A (SAA), a polyphenol from Salvia species, was tested for its ability to inhibit ferroptosis and attenuate atherosclerosis, and its molecular mechanism was investigated. Screening of 124 natural compounds identified SAA as the most potent inhibitor of RSL3-induced ferroptosis in human umbilical vein endothelial cells (HUVECs). Cellular/mitochondrial lipid peroxidation, Fe²⁺ content, ROS, and mitochondrial function were assessed with or without SAA. AMPK signaling was probed using pharmacological inhibitors. The AdipoR1 axis was examined via siRNA knockdown. In vivo, ApoE^-/- mice on a Western diet were treated with SAA to evaluate atherosclerosis and ferroptotic damage. SAA was identified as the most potent inhibitor of (1S,3R)-RSL3-induced ferroptosis in HUVECs among the screened natural compounds. SAA inhibited the ferroptotic response by restoring GPX4-dependent antioxidant capacity and preventing lipid peroxidation at both the cellular and mitochondrial levels. It improved mitochondrial function by restoring homeostasis of the mitochondrial quality control system, inhibiting mitochondrial reactive oxygen species generation, reducing ferrous iron accumulation, limiting mitochondrial lipid peroxidation, and preserving mitochondrial ultrastructure. The protective effects of SAA against ferroptosis were abolished by AMPK inhibitors, which disrupted cellular lipid metabolism and mitochondrial function regulation. The deleterious effects of AMPK inhibition were reversed by co-treatment with the mitochondrial reactive oxygen species inhibitor MitoTempol. Knockdown of AdipoR1 and experiments with the AMPK agonist AICAR confirmed that salvianolic acid A restores mitochondrial homeostasis and inhibits ferroptosis specifically through activation of the AdipoR1-AMPK signaling pathway. In vivo, treatment with SAA significantly ameliorated Western diet-induced atherosclerosis and ferroptosis-like cell damage in ApoE^-/- mice. SAA has strong therapeutic potential against endothelial ferroptosis and atherosclerosis by restoring mitochondrial homeostasis through AdipoR1-AMPK pathway activation. These findings support further clinical investigation of SAA for treating atherosclerosis and other endothelium-related cardiovascular diseases.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":"5831-5852"},"PeriodicalIF":8.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148472095","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}