Journal of Natural Medicines最新文献

{"title":"Ginsenoside Rh3-induced neurotoxicity involving the IP3R-Ca2+/NOX2/NF-κB signaling pathways","authors":"Yuheng Wang,&nbsp;Jianwen Chen,&nbsp;Song Li,&nbsp;Zhengxu Cai","doi":"10.1007/s11418-025-01912-8","DOIUrl":"10.1007/s11418-025-01912-8","url":null,"abstract":"<div><p>Ginsenoside Rh3, a bioactive component of ginsenosides, has gained attention for its potential therapeutic effects, especially in cancer treatment. However, its neurotoxic effects remain poorly characterized, raising concerns about its safety for clinical use. This study investigates the neurotoxic effects of ginsenoside Rh3 and explores the underlying mechanisms. We demonstrate that ginsenoside Rh3 induces significant cytotoxicity in Neuro-2a and C8-D1A cells, as confirmed by methyl thiazolyl tetrazolium (MTT) assays, live–dead staining, and lactate dehydrogenase (LDH) release assays. Neurotoxicity polymerase chain reaction (PCR) array analyses show that the cytotoxicity of ginsenoside Rh3 in Neuro-2a cells involves calcium ion transport, oxidative stress, inflammation, and programmed cell death (PCD). Specifically, ginsenoside Rh3 elevates intracellular Ca²⁺ levels by activating the inositol 1,4,5-triphosphate receptor (IP3R), which in turn increases oxidative stress via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) 2. This cascade activates the phosphorylated nuclear factor-kappa B (NF-κB) signaling pathway, exacerbating apoptosis and leading to neuronal cell death. Molecular docking and dynamics simulations suggest direct interactions between ginsenoside Rh3 and both IP3R and NOX2. Notably, the neurotoxic effects of ginsenoside Rh3 were significantly attenuated by IP3R inhibitor 2-aminoethyl diphenylborinate (2-APB) and NOX2 inhibitor GSK2795039. These findings demonstrate that ginsenoside Rh3 induces neurotoxicity through IP3R-Ca²⁺/NOX2/NF-κB signaling pathways. This study provides critical insights into the safety concerns of ginsenoside Rh3, highlighting the need for caution in its clinical applications.</p><h3>Graphical abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":654,"journal":{"name":"Journal of Natural Medicines","volume":"79 4","pages":"791 - 806"},"PeriodicalIF":2.5,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loganin ameliorates left ventricular fibrosis and dysfunction induced by pressure overload via the Sirt1/AKT/TGF-β1 signaling pathway","authors":"Changbin Wang,&nbsp;Xiaoli Jiang,&nbsp;Shuhua Han,&nbsp;Huimei Zang,&nbsp;Xiaoyuan Gao","doi":"10.1007/s11418-025-01911-9","DOIUrl":"10.1007/s11418-025-01911-9","url":null,"abstract":"<div><p>Loganin (LG), a natural compound derived from <i>Cornus officinalis</i> Sieb. et Zucc., possesses diverse pharmacological properties, such as anti-inflammatory, anti-hypertrophic, and antioxidant effects. However, the role of LG in the pathogenesis of Heart Failure (HF) remains unclear. The current work aimed to explore the underlying mechanism of LG in pressure overload-induced HF, both in vivo and in vitro, using transverse aortic constriction (TAC) surgery or isoproterenol (ISO) administration. Following eight weeks of TAC surgery, histological assessments, including hematoxylin and eosin staining, wheat germ agglutinin staining, TUNEL assay, and Masson’s trichrome staining, were conducted to evaluate the extent of cardiomyocyte remodeling. Additionally, RT-PCR and WB analyses were performed to detect the levels of various targets. Furthermore, H9C2 cardiomyocytes were treated with ISO to induce hypertrophy, and the effects of LG on cell viability, α-smooth muscle actin (α-SMA) expression, and molecular targets were investigated. Our findings revealed that LG treatment at 40 mg/kg/day significantly attenuated cardiac dysfunction, decreased left ventricular collagen deposition in both interstitial and perivascular spaces. Mechanistically, LG mitigated ISO-induced toxicity in H9C2 cardiomyocytes, decreasing cellular hypertrophy and α-SMA expression. Moreover, we observed a downregulation of Sirtuin 1 (Sirt1) at the molecular level, accompanied by reduced phosphorylation of Akt and transforming growth factor-β1 (TGF-β1). Notably, the administration of the Sirt1 inhibitor, EX527, effectively abolished the protective effects of LG. Therefore, the cardio-protective effects of LG were mediated through the activation of the Sirt1/Akt/TGF-β1 signaling pathway, leading to reduced fibrosis and improved cardiac function.</p><h3>Graphical abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":654,"journal":{"name":"Journal of Natural Medicines","volume":"79 4","pages":"773 - 790"},"PeriodicalIF":2.5,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chlorinated illudalane sequiterpenoids from Saxiglossum angustissimum","authors":"Yu-ting Chen,&nbsp;Jian-hua Hong,&nbsp;Cai-ying Peng,&nbsp;Jian-qun Liu,&nbsp;Yu-ye Zhu,&nbsp;Ji-cheng Shu","doi":"10.1007/s11418-025-01910-w","DOIUrl":"10.1007/s11418-025-01910-w","url":null,"abstract":"<div><p>Eight chlorinated illudalane sesquiterpenoids were isolated from the aerial parts of <i>Saxiglossum angustissimum</i>, including a pair of new pterosin enantiomers, (2<i>R</i>)-angupterosin (<b>1</b>) and (2<i>S</i>)-angupterosin (<b>2</b>), as well as a new pteroside, angupteroside (<b>3</b>). The structures of these compounds were determined through comprehensive analysis of HRESI-MS, NMR spectral data, ECD, and comparisons with previously reported literature. Remarkably, these chlorine-containing compounds (<b>1</b>–<b>8</b>) are rare and represent the first discovery of such metabolites within the family Pyrrosioideae. The chlorinated illudalane sesquiterpenoids from <i>S. angustissimum</i> may serve as valuable chemotaxonomic markers for this species. Furthermore, compounds <b>1</b>–<b>8</b> demonstrated inhibitory effects on LPS-induced NO release in BV2 cells, highlighting their potential anti-inflammatory properties.</p><h3>Graphical abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":654,"journal":{"name":"Journal of Natural Medicines","volume":"79 4","pages":"931 - 937"},"PeriodicalIF":2.5,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Amyloid-β aggregation inhibitory activity of triterpene saponins from the cactus Stenocereus gummosus","authors":"Tatsumi Matsumoto,&nbsp;Koji Fujihara,&nbsp;Tomomi Inayama,&nbsp;Hiroaki Sasaki,&nbsp;Kaoru Kinoshita","doi":"10.1007/s11418-025-01905-7","DOIUrl":"10.1007/s11418-025-01905-7","url":null,"abstract":"<div><p>Seven new triterpene saponins (<b>1</b>–<b>7</b>) and two known saponins (<b>8</b>, <b>9</b>) were isolated from MeOH extracts of <i>Stenocereus gummosus</i> (Engelm.) A.C.Gibson &amp; K.E.Horak. The structures of the isolated saponins were elucidated using MS, IR and comprehensive NMR measurements. To develop drugs for treating Alzheimer's disease (AD) based on the amyloid cascade hypothesis, the isolated saponins were evaluated for inhibition of amyloid beta (Aβ) aggregation using the thioflavin-T (Th-T) assay. Among the isolated saponins, weak activity was observed for compounds<b> 1</b>, <b>2</b>, <b>8</b> and <b>9</b> (IC₅₀ = 39.0, 36.7, 39.5, and 35.7 µM, respectively). The aglycons of the isolated saponins, gummosogenin and alamosenogenin, also showed inhibitory activity related to Aβ aggregation (IC₅₀ = 14.9 and 15.5 µM, respectively).</p><h3>Graphical abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":654,"journal":{"name":"Journal of Natural Medicines","volume":"79 4","pages":"738 - 749"},"PeriodicalIF":2.5,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oleanane-type triterpene saponins promote extracellular vesicle secretion of human adipose-derived mesenchymal stem cells","authors":"Jianyu Lin,&nbsp;Hongqiang Lin,&nbsp;Kohei Sato,&nbsp;Atsushi Kimishima,&nbsp;Satoru Tamura,&nbsp;Kazuki Ujiie,&nbsp;Chitose Oneyama,&nbsp;Jinping Liu,&nbsp;Masayoshi Arai","doi":"10.1007/s11418-025-01908-4","DOIUrl":"10.1007/s11418-025-01908-4","url":null,"abstract":"<div><p>The application of mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) holds significant promise in anti-aging cosmetics, regenerative medicine, and drug delivery systems. However, their limited production efficiency remains a critical barrier to advancing related therapies and pharmaceutical applications. In this study, a library of triterpene saponins was screened, leading to the re-discovery of an oleanane-type triterpene saponin Lucyoside H (<b>1</b>), along with its structural analogs, Chikusetsusaponins IVa (<b>2</b>), IV (<b>3</b>), and V (<b>4</b>), which were found to increase the production of EV from human adipose-derived mesenchymal stem cells (ADMSCs) at a concentration ranging from 10 to 100 µM. A comparative analysis of the chemical structures and activities of all evaluated compounds, along with oleanolic acid (<b>5</b>), revealed that (i) disubstitution of glycosyl on <i>C</i>-3 and <i>C</i>-28 of oleanane aglycone was crucial to the promoting effect; (ii) 3-<i>O</i>-<i>β</i>-<i>D</i>-glucuronopyranosyl substitution achieved the highest efficiency in the promoting effect and alteration of this group attenuated the activity. These results highlight the potential for developing a natural product-based approach to increase EV production by MSCs.</p><h3>Graphical abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":654,"journal":{"name":"Journal of Natural Medicines","volume":"79 4","pages":"922 - 930"},"PeriodicalIF":2.5,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of specialized metabolites from Artocarpus lacucha as potent α-glucosidase and acetylcholinesterase inhibitors: enzyme kinetic, in vitro and in silico study","authors":"Weerasak Songoen,&nbsp;Witthawat Phanchai,&nbsp;Johann Schinnerl,&nbsp;Lothar Brecker,&nbsp;Morakot Thabpho,&nbsp;Sorachat Tharamak,&nbsp;Wanchai Pluempanupat,&nbsp;Siriphan Sukkhaeng,&nbsp;Sasiwimol Chansuthep","doi":"10.1007/s11418-025-01904-8","DOIUrl":"10.1007/s11418-025-01904-8","url":null,"abstract":"<div><p><i>Artocarpus</i> species play an important role in the folk medicine of various ethnic groups in Africa, South Asia, and Southeast Asia. In the present study, we investigated the potential of <i>Artocarpus lacucha</i> in the treatment of diabetes mellitus and Alzheimer’s disease. During this work, one previously undescribed compound (<b>1</b>), along with 10 known compounds (<b>2</b>–<b>11</b>), were isolated from the leaves of <i>Artocarpus lacucha</i>. Their molecular structures were established using NMR and HRMS experiments. Among the tested compounds, flavan-benzofuran artocarpinol B, displayed significant α-glucosidase inhibitory activity with an IC₅₀ value of 4.01 ± 0.04 µM (positive control acarbose: 475.14 ± 4.65 µM). The conducted enzyme kinetic study revealed their inhibition mode through competitive type. This is also supported by the molecular docking and dynamics simulations which gave insight into the interactions and stability between α-glucosidase and artocarpinol B in the active site. In addition, 4-geranyl-2′,3,4′,5-tetrahydroxy-<i>trans</i>-stilbene (<b>5</b>) further shows potent acetylcholinesterase inhibition, with IC₅₀ = 8.57 ± 0.39 µM. Compounds <b>5</b> and <b>6</b> displayed moderate activity against <i>Staphylococcus aureus</i> and <i>Streptococcus agalactiae</i>, with MIC and MBC values ranging from 26.9 to 69.9 μM. This study explored the potential of constituents from <i>A. lacucha</i> as α-glucosidase and acetylcholinesterase inhibitors, which are crucial in the treatment of Diabetes mellitus and Alzheimer’s disease.</p><h3>Graphical abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":654,"journal":{"name":"Journal of Natural Medicines","volume":"79 4","pages":"896 - 912"},"PeriodicalIF":2.5,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanism study of the effects of astragaloside IV and quercetin on idiopathic pulmonary fibrosis","authors":"Ye Luo,&nbsp;Chang-jun Xu,&nbsp;Xing-hui Ai,&nbsp;Yu-ping Li,&nbsp;Xing Zhu,&nbsp;Chang-fu Yang","doi":"10.1007/s11418-025-01896-5","DOIUrl":"10.1007/s11418-025-01896-5","url":null,"abstract":"<div><p>This study aimed to investigate the effects of astragaloside IV(AS-IV) and quercetin (QCT) on autophagic activity, pyroptosis, and epithelial-mesenchymal transdifferentiation (EMT) in the context of idiopathic pulmonary fibrosis (IPF), utilizing both in vivo and in vitro models. In the in vivo component of the research, C57BL/6 J mice were subjected to bleomycin (BLM) modeling, followed by AS-IV + QCT intervention at low, medium, and high doses for 14 and 28 days. Pathological changes in lung tissue were assessed through HE and Masson staining. Additionally, the expression levels of autophagy and pyroptosis-related proteins in serum and bronchoalveolar lavage fluid were examined via Western blot analysis. In the in vitro experiment, RAW264.7 macrophage cells were co-cultured with MLE-12 alveolar epithelial cells (3:1 ratio), implementing BLM and NLR family pyrin domain-containing protein (NLRP3) + BLM models to induce IPF. The effects of AS-IV and QCT on these cells were evaluated by electron microscopy to observe structural changes, while Western blot and ELISA were used to measure the expression of autophagy and pyroptosis-related proteins. Results showed that AS-IV and QCT significantly enhanced autophagic activity, evidenced by increased levels of LC3II and beclin-1 and decreased levels of P62. Additionally, both compounds reduced the expression of pyroptosis-related proteins (NLRP3, Caspase-1, IL-1β, and IL-18) and slowed the progression of EMT in alveolar epithelial cells. These findings propose that AS-IV and QCT inhibit the EMT process in IPF by activating autophagic mechanisms while suppressing pyroptosis, thereby underscoring their potential as innovative therapeutic strategies for IPF and highlighting the promising implications of herbal compounds in its prevention and treatment.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":654,"journal":{"name":"Journal of Natural Medicines","volume":"79 4","pages":"879 - 895"},"PeriodicalIF":2.5,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Natural products that target p53 for cancer therapy","authors":"Sachiko Tsukamoto","doi":"10.1007/s11418-025-01906-6","DOIUrl":"10.1007/s11418-025-01906-6","url":null,"abstract":"<div><p>Wild-type p53 acts as a tumor suppressor, but p53 is frequently mutated and inactivated in tumor cells, promoting cancer progression, invasion, and metastasis. Thus, compounds that reactivate p53 may be leveraged for cancer treatment, and the development of drugs targeting p53 reactivation is actively progressing. Notably, natural products exhibit diverse structures and biological activities and are used as therapeutic agents for various diseases worldwide. This review discusses the natural products that inhibit p53 degradation through p53–Mdm2 interaction, promote p53 reactivation by inducing conformational changes, and exhibit p53-dependent growth inhibition.</p><h3>Graphical abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":654,"journal":{"name":"Journal of Natural Medicines","volume":"79 4","pages":"725 - 737"},"PeriodicalIF":2.5,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12228663/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957796","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring anti-hyperglycemic potential of Pseuderanthemum crenulatum: isolation, structural elucidation and α-glucosidase inhibition evaluation","authors":"Dung V. Ngo,&nbsp;Le-Thu T. Nguyen,&nbsp;Ngoc T. N. Ngo,&nbsp;Lien-Hoa D. Nguyen,&nbsp;Binh T. D. Trinh","doi":"10.1007/s11418-025-01907-5","DOIUrl":"10.1007/s11418-025-01907-5","url":null,"abstract":"<div><p><i>Pseuderanthemum crenulatum</i> (Acanthaceae) is a medicinal plant traditionally used to manage diabetes. However, its chemical constituents remain unexplored as no studies have been conducted on this species to date. This study aimed to chemically characterize and evaluate the anti-hyperglycemic activity of compounds isolated from the stems and roots of <i>P. crenulatum</i>. The isolation process involved utilizing column chromatography techniques, while structures were characterized mainly by 1D and 2D NMR experiments. Anti-hyperglycemic activity was evaluated by measuring their inhibitory effects on the <i>α</i>-glucosidase enzyme. Following this, a new abietane-type dinorditerpenoid, namely pseuderanthemone (<b>1</b>), along with ten known compounds (<b>2</b>–<b>11</b>), was isolated from an ethyl acetate extract of the stems and roots of <i>P. crenulatum</i>. The investigation into their anti-hyperglycemic effects revealed that compounds <b>1–3</b>, and <b>6–10</b> showed higher <i>α</i>-glucosidase inhibitory activity than positive control, acarbose. Among them, compound <b>9</b> demonstrated the most potent activity, with an IC₅₀ value nearly ten times lower than acarbose. Furthermore, kinetic analysis showed that compound <b>2</b> displayed mixed-type inhibition, and compound <b>3</b> demonstrated uncompetitive inhibition while the remaining compounds exhibited competitive inhibition.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":654,"journal":{"name":"Journal of Natural Medicines","volume":"79 4","pages":"913 - 921"},"PeriodicalIF":2.5,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dendrobium huoshanense polysaccharide inhibits NSCLC proliferation and immune evasion via FXR1-IL-35 axis signaling pathway","authors":"Xinying Zhu,&nbsp;Guoquan Yin,&nbsp;Jiaqian Xu,&nbsp;Xiaolei Tang,&nbsp;Fangliu Yu","doi":"10.1007/s11418-025-01894-7","DOIUrl":"10.1007/s11418-025-01894-7","url":null,"abstract":"<div><p>Dendrobium huoshanense has received special attention for its advantages in the treatment of lung cancer, but the underlying molecular mechanisms are not yet well understood. First, we obtained 8 active ingredients and 159 effective action targets of Dendrobium huoshanense using network pharmacology, and searching target interactions through STRING, constructing the PPI network and KEGG, GO and Hallmark enrichment analysis. Then, we combined target’s enrichment analysis and GSEA enrichment analysis of IL-35, indicating the mechanism of cDHPs for non-small cell lung cancer (NSCLC) may be related to tight junction and NSCLC pathway. Further, FXR1 and ACTR3 were identified as core therapeutic targets, and high expression of FXR1 or ACTR3 was significantly associated with poor prognosis of patients. The analysis of single-cell data also indicated that the percentage of CD4-CTLA4-Treg cells may be increased by the expression of IL-35, resulting in a suppressive immune microenvironment. Next, In vivo experiment, we detected iTr35 by flow cytometry, detected IL-35 level by RT-PCR, Western blotting and ELISA, and detected NK cell activity to explore the immunomodulatory effects and anti-tumor mechanism of cDHPs. After cDHPs administration, the conversion of CD4⁺ T cells to iTr35 is inhibited, p35 and EBI3 in both protein and mRNA levels, the levels of IL-35 and IL-4 in serum decreased. The levels of IFN-γ, while the activity of NK cells in mice increased, enhancing the anti-tumor immune effect of the organism. Finally, analysis of sequencing data from the immunotherapy cohort of tumor-bearing mice obtained from the TISMO database shows that the combination of cDHPs and PD-1/PD-L1 antibodies improves effector and thus PD-1/PD-L1 antibody efficacy. These findings suggest that cDHPs inhibit NSCLC proliferation and immune escape via the FXR1-IL-35 axis signaling pathway.</p><h3>Graphical abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":654,"journal":{"name":"Journal of Natural Medicines","volume":"79 4","pages":"863 - 878"},"PeriodicalIF":2.5,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12228671/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143967686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}