Phytomedicine最新文献

{"title":"Bupleurum chinense ameliorates metabolic-associated fatty liver disease by modulating Sirtuin 6","authors":"Siqi Liu ,&nbsp;Penglong Chen ,&nbsp;Yayi Li ,&nbsp;Zhisen Pan ,&nbsp;Can Zhang ,&nbsp;Anquan Li ,&nbsp;Chongyan Huang ,&nbsp;Hongxuan Zheng ,&nbsp;Like Chen ,&nbsp;Chuangpeng Shen","doi":"10.1016/j.phymed.2026.157905","DOIUrl":"10.1016/j.phymed.2026.157905","url":null,"abstract":"<div><h3>Background</h3><div><em>Bupleurum chinense</em> (Bc) is a traditional Chinese medicine commonly used to treat metabolic-associated fatty liver disease (MAFLD), demonstrating hepatoprotective, anti-inflammatory, and antioxidant effects. Sirtuin 6 (SIRT6) regulates fatty acid metabolism and oxidative stress, playing a crucial role in MAFLD treatment.</div></div><div><h3>Purpose</h3><div>To investigate Bc’s mechanisms in ameliorating MAFLD and analyze the primary active components contributing to its therapeutic effects.</div></div><div><h3>Methods</h3><div>C57BL/6J mice developed MAFLD through 12-week high-fat diet (HFD) feeding, followed by 4-week interventions with Bc decoction (1.3, 0.65, 0.325 g/kg/d) or pioglitazone (0.1 g/kg/d). Lipid metabolism, oxidative stress, inflammation, and insulin resistance were measured. RNA-seq identified the key Bc targets, which were validated in liver-specific knockout mice. Bioactive constituents were initially screened using the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database, followed by molecular docking, dynamics simulations, and microscale thermophoresis (MST) to validate target affinity and binding stability. An in vitro MAFLD model was established using primary mouse hepatocytes (MPHs) challenged with oleic and palmitic acid (OAPA).</div></div><div><h3>Results</h3><div>Bc significantly ameliorated lipid accumulation and HFD-induced oxidative stress. Pioglitazone and Bc (1.3 g/kg/d) administration demonstrated marked reductions in circulating TG, ALT, and AST concentrations in a dose-responsive manner. Furthermore, Bc ameliorated hepatic oxidative stress, as evidenced by elevated GSH and SOD levels alongside reduced H₂O₂ content. Transcriptomic profiling and mechanistic validation identified SIRT6 as the central mediator. Bc upregulated SIRT6 expression and enhanced its deacetylase activity, resulting in reduced acetylation of histone H3K9 and H3K56 compared to HFD controls. This promoted PPARα/NRF2 nuclear translocation, upregulating fatty acid β-oxidation genes (such as <em>Cpt1a</em>) and antioxidant genes (such as <em>Ho-1</em>). Crucially, hepatocyte-specific Sirt6 knockout abolished Bc's therapeutic effects. Moreover, molecular docking, molecular dynamics, and MST results indicated that Saikosaponin C (SSc), the major component of Bc, has a strong affinity for SIRT6. Cell experiments confirmed that SSc (25 μM) significantly improved lipid deposition and redox imbalance in MAFLD models, exhibiting SIRT6-dependent efficacy.</div></div><div><h3>Conclusion</h3><div>Bc alleviates MAFLD by activating SIRT6 through its core component SSc. This activation, via SIRT6-mediated histone deacetylation, enhances PPARα/NRF2-driven metabolic-redox homeostasis, establishing the Bc-SSc-SIRT6 axis as a therapeutic target.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"153 ","pages":"Article 157905"},"PeriodicalIF":8.3,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146158089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Da-Bu-Yin-Wan rescues cognitive deficits in aging and Alzheimer’s disease models by Wnt/β-catenin-dependent restoration of lysosomal acidification","authors":"Haijun Zhang ,&nbsp;Hao Zhang ,&nbsp;Meihuan Zhao ,&nbsp;Wenjun Luo ,&nbsp;Simin Chen ,&nbsp;Ping Wang ,&nbsp;Xiao Liu ,&nbsp;Shijun Xu","doi":"10.1016/j.phymed.2026.157916","DOIUrl":"10.1016/j.phymed.2026.157916","url":null,"abstract":"<div><h3>Background</h3><div>Lysosomal acidification deficits are increasingly recognized as a convergent pathological mechanism driving both age-related cognitive decline (ARCD) and early Alzheimer's disease (AD) progression, creating a self-reinforcing cycle of cellular aging and Aβ dyshomeostasis. Despite demonstrated neuroprotective effects of Da-Bu-Yin-Wan (DBYW) in Parkinson's disease models, its therapeutic potential for lysosomal dysfunction in ARCD and AD remains an uncharted area of investigation.</div></div><div><h3>Purpose</h3><div>This present work aimed to elucidate the mechanistic basis by which DBYW mitigates both ARCD and AD pathology through functionally rescuing impaired lysosomal acidification.</div></div><div><h3>Methods</h3><div>Cell-based D-galactose and Aβ-induced in BV2 cells to study lysosomal acidification. Molecular analyses combined immunofluorescence localization studies with quantitative immunoblotting of lysosomal and Wnt signaling proteins. <em>In vivo</em>, DBYW treatment effects were systematically evaluated in both D-gal-induced and APP/PS1 transgenic models using cognitive behavioral followed by immunohistochemical and biochemical assessment of brain tissues lysosomal parameters and Wnt signaling activity.</div></div><div><h3>Results</h3><div>DBYW attenuated the mechanistic basis of ARCD and AD pathology by functionally rescuing impaired lysosomal acidification. Overexpression of β-catenin could modulate D-galactose or Aβ-induced dysregulation of the Wnt/β-catenin pathway and restore lysosomes with abnormal acidification, while DBYW could regulate lysosomal function by promoting Wnt/β-catenin signaling. In addition, in D-gal-induced aging and AD model mice, DBYW treatment activated Wnt/β-catenin signaling to restore lysosomal acidification, while spatial memory deficits in ARCD and AD models were improved, and pathology in mouse attenuation and APP/PS1 mouse brain tissue was inhibited.</div></div><div><h3>Conclusion</h3><div>DBYW shows a potential dual efficacy in improving cognitive decline in ARCD and AD models. It makes DBYW a promising disease-modifying intervention targeting the shared lysosomal pathophysiology of aging-associated neurodegeneration.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"153 ","pages":"Article 157916"},"PeriodicalIF":8.3,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146150424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quercetagitrin targets EIF3D to activate NCOA4-mediated ferritinophagy-dependent ferroptosis for the treatment of non-small cell lung cancer","authors":"Xinglinzi Tang ,&nbsp;Feiyan Wu ,&nbsp;Huijuan Rao ,&nbsp;Xinyi Luo ,&nbsp;Guixing Zhang ,&nbsp;Xin Lai ,&nbsp;Caizhi Li ,&nbsp;Jiansong Fang ,&nbsp;Hang Li","doi":"10.1016/j.phymed.2026.157914","DOIUrl":"10.1016/j.phymed.2026.157914","url":null,"abstract":"<div><h3>Background</h3><div>Non-small cell lung cancer (NSCLC) is the predominant subtype of lung cancer. Although traditional treatment methods such as surgery, chemotherapy, and radiotherapy can extend patient survival to some extent, they still present significant challenges due to their limited efficacy and substantial side effects. Ferroptosis, a form of iron-dependent programmed cell death, has been shown to exhibit considerable potential in the treatment of NSCLC. However, the molecular mechanisms underlying ferroptosis and how to safely and effectively induce it remain to be fully explored. This study aims to investigate the mechanism by which the natural flavonoid compound Quercetagitrin (Que) regulates the ferritinophagy-ferroptosis pathway to suppress NSCLC and to identify its molecular targets.</div></div><div><h3>Methods</h3><div>This study evaluated the selective toxicity of Que against NSCLC cells (A549, PC9) and normal lung epithelial cells (BEAS-2B) using <em>in vitro</em> assays, including CCK-8, colony formation, and flow cytometry. Key pathways related to ferritinophagy and ferroptosis were identified through transcriptomic analysis and KEGG pathway analysis. Fluorescence imaging, Western blot (WB) and BODIPY C11 staining were used to assess the levels of ferritinophagy and ferroptosis in cells. Limited proteolysis-mass spectrometry (LiP-MS) and molecular dynamics simulations were employed to identify the direct targets of Que. Gene knockdown and overexpression experiments were conducted to verify that Que targets eukaryotic translation initiation factor 3 subunit D (EIF3D) and regulates the activation of nuclear receptor coactivator 4 (NCOA4) -mediated ferritinophagy. <em>In vivo</em> experiments using xenograft mouse models assessed the antitumor effect and safety of Que.</div></div><div><h3>Results</h3><div>Que selectively inhibited the proliferation and colony formation of NSCLC cells while showing minimal toxicity to normal lung epithelial cells. It promoted the release of Fe²⁺ and lipid peroxidation by activating the NCOA4-dependent ferritinophagy pathway, while simultaneously inhibiting the expression of ferroptosis markers such as glutathione peroxidase 4 (GPX4). LiP-MS and molecular dynamics simulations confirmed EIF3D as a direct target of Que. Knockdown of EIF3D mimicked the antitumor effect of Que, whereas overexpression of EIF3D diminished its antitumor effect. <em>In vivo</em>, Que significantly inhibited tumor growth without observable toxicity, accompanied by upregulation of NCOA4 and LC3 II, and downregulation of EIF3D and GPX4.</div></div><div><h3>Conclusion</h3><div>Que exerts significant antitumor effects in NSCLC by targeting EIF3D to activate NCOA4-mediated ferritinophagy and ferroptosis. This study reveals a novel mechanism involving the EIF3D-NCOA4 axis in the regulation of ferritinophagy-dependent ferroptosis, providing a potential therapeutic strategy for the treatment of NSCLC.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"153 ","pages":"Article 157914"},"PeriodicalIF":8.3,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146137817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genistein ameliorates lupus nephritis via enhancing ERβ-mediated inhibition of STAT3-driven inflammation","authors":"Jieli Pan ,&nbsp;Jinjun Ji ,&nbsp;Xingpan Xin ,&nbsp;Yihong Gan ,&nbsp;Zixin Huang ,&nbsp;Jing Chen ,&nbsp;Ying Li ,&nbsp;Jie Bao ,&nbsp;Yujun Tang ,&nbsp;Chengping Wen ,&nbsp;Li Xu","doi":"10.1016/j.phymed.2026.157917","DOIUrl":"10.1016/j.phymed.2026.157917","url":null,"abstract":"<div><h3>Background</h3><div>Systemic lupus erythematosus (SLE) is an autoimmune disease with marked female predominance. Lupus nephritis (LN), one of its most severe manifestations, is strongly associated with aberrant activation of signal transducer and activator of transcription 3 (STAT3). Estrogen receptor β (ERβ) has been reported to exert immunoregulatory effects, but its role in restraining STAT3 signaling in LN remains unclear.</div></div><div><h3>Purpose</h3><div>This study aimed to investigate whether genistein, a phytoestrogen with selective affinity for ERβ, can modulate the ERβ–STAT3 axis to attenuate lupus nephritis.</div></div><div><h3>Methods</h3><div>The therapeutic effects of genistein were evaluated in MRL/lpr and pristane-induced lupus mouse models and in LPS-stimulated macrophages. Macrophage polarization, oxidative stress, mitochondrial function, and ERβ–STAT3 signaling were assessed using flow cytometry, biochemical assays, immunoblotting, and bioinformatic analyses.</div></div><div><h3>Results</h3><div>Genistein significantly ameliorated renal injury, reduced proteinuria, and decreased serum autoantibody and IL-6 levels in lupus models. Mechanistically, genistein suppressed M1 macrophage polarization by activating ERβ and inhibiting STAT3 and NF-κB signaling. Genistein also attenuated oxidative stress by preserving mitochondrial membrane potential, reducing reactive oxygen species production, and restoring antioxidant capacity. Pharmacological blockade of ERβ markedly attenuated the anti-inflammatory effects of genistein, confirming ERβ-dependent regulation of STAT3 signaling.</div></div><div><h3>Conclusion</h3><div>This study identifies ERβ as a negative regulator of STAT3-driven inflammation and demonstrates that genistein therapeutically engages this axis to suppress macrophage-mediated renal injury, offering a promising therapeutic strategy for lupus nephritis.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"153 ","pages":"Article 157917"},"PeriodicalIF":8.3,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146137850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative effects of Bacopa monnieri and Ginkgo biloba on cognitive functions: A systematic review and network meta-analysis","authors":"Pailada Tiemtad ,&nbsp;Kornkanok Ingkaninan ,&nbsp;Prapapan Temkitthawon ,&nbsp;Phiyanuch Thimkorn ,&nbsp;Natnicha Rattanachaisit ,&nbsp;Thanasak Teaktong ,&nbsp;Teerapon Dhippayom","doi":"10.1016/j.phymed.2026.157915","DOIUrl":"10.1016/j.phymed.2026.157915","url":null,"abstract":"<div><h3>Background</h3><div>Growing cognitive health interest fuels 8.3% market growth. <em>Bacopa monnieri</em> Wettst. (Brahmi) and <em>Ginkgo biloba</em> L. (Ginkgo) are among the most studied natural nootropics, but their effects have not been directly compared. This study aimed to evaluate and compare their efficacy in healthy adults using a network meta-analysis.</div></div><div><h3>Methods</h3><div>We searched PubMed, EMBASE, Cochrane CENTRAL, and EBSCO Open Dissertations in November 2024. Randomized controlled trials (RCTs) on healthy adults receiving Brahmi or Ginkgo extracts and reported cognitive outcomes were included. Risk of bias was assessed using the Cochrane Risk of Bias version 2. Cognitive outcomes were analyzed using standardized mean differences (SMDs) with 95% confidence intervals (CI) under a random-effects model. Interventions were ranked using the surface under the cumulative ranking curve (SUCRA).</div></div><div><h3>Results</h3><div>Twenty-nine RCTs (<em>n</em> = 2107) were included. High-dose Brahmi (≥600 mg/day) significantly improved working memory compared to low-dose Brahmi (300 to &lt;600 mg/day), high-dose Ginkgo (≥240 mg/day), low-dose Ginkgo (60 to &lt;240 mg/day), and placebo, with SMDs (95% CI) of 1.84 (1.05–2.64), 1.94 (1.10–2.77), 2.04 (1.24–2.84), and 2.03 (1.28–2.78), respectively. A SUCRA of 100% further supports the strong efficacy of high-dose Brahmi. It also demonstrated significantly greater benefits for short-term memory. For delayed memory, low-dose Brahmi outperformed both low-dose Ginkgo and placebo. No significant differences were observed in sustained attention, selective attention, or processing speed.</div></div><div><h3>Conclusion</h3><div>Brahmi, particularly in high-dose formulations, shows promise as a cognitive enhancer compared to Ginkgo in healthy adults. However, the lack of direct comparisons may limit the strength of this evidence.</div></div><div><h3>Other</h3><div>The authors are grateful for financial support from The Royal Golden Jubilee Ph.D. Program (RGJ-Ph.D. Program), Thailand Research Fund (TRF) (N41A670299). This study is registered with PROSPERO (CRD420251034900).</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"153 ","pages":"Article 157915"},"PeriodicalIF":8.3,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146181906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Zhi-Chuan-Ling alleviates OVA-induced allergic asthma by suppressing M2 macrophage polarization via the PI3K/AKT/mTOR/STAT6 pathway","authors":"Sihui Xing ,&nbsp;Huidan Chen ,&nbsp;Ling Wang ,&nbsp;Siye Lv ,&nbsp;Jinpu Zhu ,&nbsp;Zhongtian Wang ,&nbsp;Jing Han ,&nbsp;Haiyang Zhang ,&nbsp;Ruikang Fang ,&nbsp;Jiali Wu ,&nbsp;Fengyan Shao ,&nbsp;Jicheng Han ,&nbsp;Liping Sun","doi":"10.1016/j.phymed.2026.157911","DOIUrl":"10.1016/j.phymed.2026.157911","url":null,"abstract":"<div><h3>Background</h3><div>Allergic asthma, predominantly driven by Th2 immune responses, is a chronic respiratory disease that poses a significant threat to human health. Zhi-Chuan-Ling (ZCL), a traditional Chinese medicine widely used for the treatment of asthma and wheezy bronchitis, has been shown to relieve airway constriction and suppress airway inflammation. However, its mechanisms in regulating macrophage polarization, a key Th2-driven inflammatory process, remain unclear.</div></div><div><h3>Purpose</h3><div>This study aimed to assess the therapeutic effects of ZCL on allergic asthma and to investigate its molecular mechanisms in modulating macrophage polarization.</div></div><div><h3>Methods</h3><div>The chemical profile of ZCL was characterized by high-performance liquid chromatography (HPLC). An ovalbumin (OVA)-induced mouse model of allergic asthma was established to assess the anti-asthmatic effects of ZCL. Mechanistic studies included hematoxylin-eosin (H&amp;E) and Masson’s trichrome (MT) staining, immunofluorescence (IF), ELISA, flow cytometry (FCM), transcriptomic profiling, Western blotting (WB), and in silico molecular docking to predict binding interactions of key ZCL compounds with target proteins involved in M2 macrophage polarization and airway inflammation.</div></div><div><h3>Results</h3><div>ZCL treatment significantly alleviated asthma symptoms and reduced airway inflammation in vivo. Mechanistically, ZCL inhibited M2 macrophage polarization by modulating the PI3K/AKT/mTOR/STAT6 signaling pathway. Molecular docking analysis revealed favorable binding of major ZCL compounds to PI3K, AKT, mTOR, and STAT6, supporting their potential role in modulating these signaling molecules.</div></div><div><h3>Conclusion</h3><div>ZCL protects against allergic asthma by suppressing M2 macrophage polarization through the PI3K/AKT/mTOR/STAT6 axis and by directly interacting with key pathway proteins, thereby attenuating airway inflammation and remodeling. These findings provide both functional and molecular evidence for the therapeutic potential of ZCL in allergic asthma.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"153 ","pages":"Article 157911"},"PeriodicalIF":8.3,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146116350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"YTHDF2-orchestrated m6A methylation of BECN1 induces Scoparone-mediated hepatic stellate cell ferroptosis to attenuate liver fibrosis","authors":"Yuqi Sun ,&nbsp;Yanshuang Zhuang ,&nbsp;Kaiwen Cheng ,&nbsp;Yuyao Wei ,&nbsp;Mengran Li ,&nbsp;Ji Xuan ,&nbsp;Shizhong Zheng ,&nbsp;Mei Guo ,&nbsp;Zili Zhang","doi":"10.1016/j.phymed.2026.157912","DOIUrl":"10.1016/j.phymed.2026.157912","url":null,"abstract":"<div><h3>Background</h3><div>Liver fibrosis represents a dynamically reversible pathological process arising as an adaptive repair response to chronic hepatic insults. Scoparone (SCO), an active constituent of artemisia, has demonstrated therapeutic potential across diverse liver diseases, but its antifibrotic mechanism remains unclear.</div></div><div><h3>Purpose</h3><div>This study aims to elucidate the molecular mechanism by which SCO ameliorates liver fibrosis through m⁶A epitranscriptomic regulation of hepatic stellate cell (HSC) ferroptosis.</div></div><div><h3>Methods</h3><div>Murine liver fibrosis models and human HSC cells were employed to evaluate the therapeutic effects of SCO on liver fibrosis. Single-cell sequencing, spatial transcriptome sequencing, transcriptome sequencing, immunoprecipitation and laser confocal were used to investigate the potential molecular mechanisms.</div></div><div><h3>Results</h3><div>Animal experiments and cellular studies showed that SCO exhibited potent antifibrotic effects, which was attributed to the induction of HSC ferroptosis through m⁶A modification. Integrative transcriptomic and bioinformatic analyses identified BECN1 as a key target for m⁶A methylation regulation of ferroptosis. Mechanistically, SCO may interact with the ASN462 residue of YTHDF2, enhancing its protein stability and expression. Elevated YTHDF2 can facilitate translation of BECN1 mRNA by recognizing m⁶A methylation at the A100 site within the 5′-UTR, leading to SLC7A11 activity inhibition and subsequent ferroptotic cell death in HSCs. Clinically, YTHDF2 and BECN1 expression was downregulated in fibrotic liver tissue specimens, which was associated with a poor prognosis.</div></div><div><h3>Conclusions</h3><div>These results reveal a novel epitranscriptomic mechanism by which SCO induces HSC ferroptosis to attenuate liver fibrosis by promoting the formation of BECN1-SLC7A11 complex through YTHDF2-mediated m⁶A modification. Thess findings molecular insights and therapeutic rationales for SCO-based antifibrotic therapies.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"153 ","pages":"Article 157912"},"PeriodicalIF":8.3,"publicationDate":"2026-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146143347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Berberine reverses impaired adipose angiogenesis to promote beige adipogenesis by HIF-1α/PRDM16 signaling","authors":"Chien-shan Cheng ,&nbsp;Jingxian Chen ,&nbsp;Yuan Wu ,&nbsp;Yijie Song ,&nbsp;Jiayue Xu ,&nbsp;Yu Xu ,&nbsp;Lan Zheng","doi":"10.1016/j.phymed.2026.157902","DOIUrl":"10.1016/j.phymed.2026.157902","url":null,"abstract":"<div><h3>Background</h3><div>Obesity-induced adipose tissue expansion is characterized by capillary rarefaction and hypoxia, which disrupts angiogenesis and impairs beige adipogenesis. While angiogenesis is known to be crucial for beiging, the functional link between impaired vascularization and defective browning remains poorly understood. How natural compounds like berberine (BBR) links angiogenesis with beige adipogenesis remains unexplored.</div></div><div><h3>Methods</h3><div>Using both diet-induced obese (DIO) C57BL/6 J and leptin-deficient (ob/ob) murine models, we administered intraperitoneal BBR for 4 weeks. Adipose tissue remodeling was evaluated through histomorphometry, immunofluorescence, and flow cytometry. RNA sequencing of adipose tissue was performed to identify the potential targets. Chemical hypoxia was induced using CoCl₂ in preadipocytes to examine its effects on browning.</div></div><div><h3>Results</h3><div>BBR improved adipose tissue dysfunction in both the DIO model and the ob/ob model. It increased CD34⁺CD31⁺ endothelial progenitor cells and enhanced protein levels of VEGF/VEGFR2, PRDM16, PPAR-γ, and UCP-1, indicating simultaneous promotion of angiogenesis and adipose browning. Transcriptomic analysis revealed glutathione peroxidase 3 (GPx3) as a novel target through which BBR alleviates adipose dysfunction. GPX3 knockdown <em>in vivo</em> impaired angiogenesis and suppressed browning markers. BBR reversed chemical hypoxia-induced impairment of beige adipocyte differentiation independently of UCP-1 upregulation by inhibiting HIF-1α activation.</div></div><div><h3>Conclusions</h3><div>This study unveils that BBR counteracts obesity-associated adipose tissue dysfunction: it upregulates GPx3 to reduce oxidative stress, which in turn normalizes HIF-1α levels and activates the PRDM16 signaling, thereby concurrently restoring adipose angiogenesis and promoting beige adipogenesis. This breaks the vicious cycle of hypoxia-impaired angiogenesis and suppressed thermogenesis, positioning BBR as a promising multi-target therapy for obesity.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"153 ","pages":"Article 157902"},"PeriodicalIF":8.3,"publicationDate":"2026-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146137866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacological targeting of NR4A1 restrains lipid metabolism–ferroptosis axis in UVR-induced skin aging","authors":"Hongjin Wang ,&nbsp;Jingjing Li ,&nbsp;Xiaogang Xu ,&nbsp;Yixi Zeng ,&nbsp;Guofeng Shi ,&nbsp;Lanyue Zhang ,&nbsp;Junxia Zheng ,&nbsp;Hui Li","doi":"10.1016/j.phymed.2026.157909","DOIUrl":"10.1016/j.phymed.2026.157909","url":null,"abstract":"<div><h3>Background</h3><div>Skin photo-aging induced by ultraviolet radiation (UVR) leads to aesthetic alterations, structural degradation, and loss of barrier function. Ferroptosis has been implicated upon UVR stress but the driving modifiers remain largely undefined. Naringin has been reported to exert protective effects against UVR damage, however, the underlying mechanisms remain incompletely understood.</div></div><div><h3>Purpose</h3><div>To explore the driving factors of UVR-induced ferroptosis and to comprehensively evaluate the effects and underlying mechanisms of naringin in repressing UVR-induced photo-aging.</div></div><div><h3>Methods</h3><div>A mouse model in which the dorsal skin, as well as a cell model using HaCaT keratinocytes, were exposed to UVR to simulate daily sun exposure. Lentivirus-mediated knockdown, ChIP-seq, and RNA-seq analysis were used to evaluate the role of NR4A1 in UVR-induced ferroptosis. RNA-seq and metabonomics were performed to elucidate the underlying mechanisms of naringin against photo-aging. Molecular dynamics simulations/DARTS/CETSA, and co-IP assays were employed to investigate the mechanism by which naringin regulates NR4A1 expression.</div></div><div><h3>Results</h3><div>Reduction of NR4A1 leads to excessive lipid metabolism and initiates ferroptosis in UVR-induced photo-aging. Naringin directly binds to NR4A1, enhancing its stability by preventing ubiquitin-mediated degradation, transcriptionally represses EGR1 and LDLR expression, thereby suppressing lipid peroxidation and ferroptotic damage. Remarkably, both genetic deficiency and pharmacological inhibition of NR4A1 across diverse models abolish the effects of naringin against photo-aging.</div></div><div><h3>Conclusion</h3><div>Our findings emphasize the critical role of NR4A1 in ferroptosis driven by dysregulated lipid metabolism and reveal the therapeutic potential of targeting NR4A1 with naringin in UVR-induced photo-aging, as well as in the other relevant lipid metabolism dysfunction disorders.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"153 ","pages":"Article 157909"},"PeriodicalIF":8.3,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146137901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pedunculoside ameliorates metabolic dysfunction-associated steatotic liver disease by targeting HNRNPA1 and modulating PPARα signaling pathway to enhance Mitochondrial Fatty Acid β-Oxidation","authors":"Yang Zhou ,&nbsp;Jingyun Chi ,&nbsp;Xining Xu ,&nbsp;Rongrong Zhu ,&nbsp;Tianhao Wang ,&nbsp;Tao Zhang ,&nbsp;Dandan Hong ,&nbsp;Huazhou Fu ,&nbsp;Xizhen Zhou ,&nbsp;Kun Zhao","doi":"10.1016/j.phymed.2026.157910","DOIUrl":"10.1016/j.phymed.2026.157910","url":null,"abstract":"<div><h3>Background</h3><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a significant global health challenge, underscoring an urgent need for novel therapeutic agents that offer enhanced efficacy and improved safety. Pedunculoside (PE), a naturally occurring triterpenoid saponin, has demonstrated promising lipid-modulating properties. Nevertheless, its precise mechanisms of action in the context of MASLD remain unclear.</div></div><div><h3>Purpose</h3><div>To investigate the anti-MASLD effect of PE and uncover its novel mechanism via targeting heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) and regulating downstream PPARα pathway.</div></div><div><h3>Method</h3><div>The therapeutic potential of PE was evaluated both in primary mouse hepatocytes and in vivo using high-fat, high-cholesterol (HFHC) and high-fat diet (HFD) induced MASLD mouse models. A multi-omics and multi-technique approach was applied, including biochemical assays, histopathology, transcriptomic and lipidomic profiling, alongside target-engagement validation via drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), surface plasmon resonance (SPR), molecular docking, molecular dynamics simulations, and HNRNPA1 knockout models.</div></div><div><h3>Results</h3><div>PE significantly improved key metabolic and histological features in MASLD models. Mechanistically, PE was found to directly bind HNRNPA1 (a previously unreported target in MASLD therapeutics). This interaction enhanced the mRNA stability of PPARα, leading to activation of fatty acid β-oxidation. Crucially, HNRNPA1 knockout abolished the beneficial effects of PE, confirming the functional necessity of the PE–HNRNPA1–PPARα axis in vivo.</div></div><div><h3>Conclusion</h3><div>Our study uncovers a novel therapeutic axis in MASLD, in which PE enhances the stability of PPARα mRNA by directly binding to HNRNPA1, and consequently upregulates fatty acid β-oxidation. These findings not only position PE as a promising therapeutic candidate for MASLD but also identify the HNRNPA1–PPARα regulatory pathway as a potential mechanistic target for treating metabolic liver diseases.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"153 ","pages":"Article 157910"},"PeriodicalIF":8.3,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146166394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}