Phytotherapy Research最新文献

Targeting Mitochondrial Dysfunction by Natural Products for the Treatment of Diabetic Kidney Disease. 利用天然产物靶向线粒体功能障碍治疗糖尿病肾病。

IF 6.3 2区医学

Phytotherapy Research Pub Date : 2025-07-30 DOI: 10.1002/ptr.70059

Jin-Ling Huo, Peipei Li, Qi Feng, Wenjia Fu, Shaokang Pan, Dongwei Liu, Zhang-Suo Liu

引用次数: 0

6-Shogaol Reduces Renal Macrophage Infiltration by Targeting the STING Pathway to Alleviate Cisplatin Induced Renal Injury. 6-Shogaol通过STING通路减少肾巨噬细胞浸润减轻顺铂所致肾损伤

IF 6.3 2区医学

Phytotherapy Research Pub Date : 2025-07-29 DOI: 10.1002/ptr.70053

Xuewei Yan, Jiaojiao Luo, Xia Chen, Lixin Wang, Zihang Xu, Chunrong Guo, Weirong Zhu, Yue Ding, Jiaye Jiang

{"title":"6-Shogaol Reduces Renal Macrophage Infiltration by Targeting the STING Pathway to Alleviate Cisplatin Induced Renal Injury.","authors":"Xuewei Yan, Jiaojiao Luo, Xia Chen, Lixin Wang, Zihang Xu, Chunrong Guo, Weirong Zhu, Yue Ding, Jiaye Jiang","doi":"10.1002/ptr.70053","DOIUrl":"https://doi.org/10.1002/ptr.70053","url":null,"abstract":"Cisplatin is a widely used chemotherapeutic agent, but its dose-limiting nephrotoxicity remains a major clinical challenge. 6-Shogaol, a bioactive compound with potent anti-inflammatory and antioxidant properties, exhibits strong binding affinity for STING-a key mediator in cisplatin-induced kidney injury. This study aims to investigate the renoprotective effects of 6-shogaol against cisplatin nephrotoxicity and elucidate its underlying mechanisms. Using a murine model of cisplatin-induced nephrotoxicity and in vitro experiments with HK-2 cells, we evaluated the cytoprotective effects of 6-shogaol. Molecular docking simulations confirmed its high binding affinity for STING. A comprehensive approach, including flow cytometry, RNA sequencing, ELISA, qPCR, histopathological staining (H&E staining), immunofluorescence, and Western blot analyses, was employed to assess renal function, tubular injury, inflammatory responses, and molecular mechanisms. CRISPR/Cas9-mediated STING knockout was performed to validate the mechanistic role of STING. 6-Shogaol significantly attenuated cisplatin-induced renal damage, as evidenced by reduced serum creatinine and blood urea nitrogen levels, diminished macrophage infiltration, and downregulated expression of CCL2 and CCL5 in renal tissues. Molecular docking revealed stable binding between 6-shogaol and STING. In vitro, 6-shogaol mitigated cisplatin-induced cellular injury, suppressed the cGAS-STING pathway, and reduced pro-inflammatory cytokine (IL-1β, IL-6, TNF-α) and chemokine (CCL2, CCL5) expression. STING knockout in HK-2 cells abolished cisplatin-induced cytotoxicity and attenuated the protective effects of 6-shogaol. These findings demonstrate that 6-shogaol alleviates cisplatin-induced kidney injury by targeting STING, thereby inhibiting CCL2/CCL5-mediated macrophage infiltration and subsequent inflammation.","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732691","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}

引用次数: 0

Salvianolic Acid B Inhibits ZBP1-Mediated PANoptosis in Mycobacterium tuberculosis-Infected Macrophages by Targeting TNFR1. 丹酚酸B通过靶向TNFR1抑制zbp1介导的结核分枝杆菌感染巨噬细胞PANoptosis

IF 6.3 2区医学

Phytotherapy Research Pub Date : 2025-07-27 DOI: 10.1002/ptr.70042

Jingjing Shen, Yan Fu, Fanglin Liu, Jianchao Wu, Hemin Zhang, Jinxia Sun, Zhulei Miao, Xin Jiang

{"title":"Salvianolic Acid B Inhibits ZBP1-Mediated PANoptosis in Mycobacterium tuberculosis-Infected Macrophages by Targeting TNFR1.","authors":"Jingjing Shen, Yan Fu, Fanglin Liu, Jianchao Wu, Hemin Zhang, Jinxia Sun, Zhulei Miao, Xin Jiang","doi":"10.1002/ptr.70042","DOIUrl":"https://doi.org/10.1002/ptr.70042","url":null,"abstract":"The increasing rates of drug resistance in Mycobacterium tuberculosis (Mtb) have made controlling tuberculosis more challenging. Excessive programmed cell death helps mediate Mtb transmission. Salvianolic acid B (Sal B), a water-soluble extract of Salvia miltiorrhiza, has been reported to inhibit programmed cell death and excessive inflammation. This study aimed to investigate the potential inhibitory mechanism of Sal B on PANoptosis. The inhibitory effect of Sal B on PANoptosis was evaluated by western blotting, ELISA, and other techniques in an in vitro model of Mtb H37Ra-infected macrophages. The roles of ZBP1 and TNFR1 in PANoptosis were explored by small interfering RNA transfection. In addition, the inhibitory effect of Sal B on PANoptosis and the hyperinflammatory response was verified by western blotting, hematoxylin and eosin staining, and immunohistochemistry in an in vivo model of inflammatory injury in the lungs of LPS-infected mice. Sal B inhibited the protein levels of key molecules of Mtb-mediated PANoptosis and hindered the assembly of the PANoptosome consisting of ASC, ZBP1, RIPK1, RIPK3, and Caspase 8. Sal B may further inhibit PANoptosis by binding to TNFR1 and suppressing ZBP1 levels. In addition, the results of in vivo studies verified that Sal B could ameliorate LPS-induced pathological injury in mouse lung tissues. Sal B can target TNFR1 to achieve a regulatory effect on macrophage PANoptosis. This provides new ideas for Sal B as a host-directed therapy drug to attenuate the excessive inflammatory response induced by Mtb infection.","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732728","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}

引用次数: 0

Reniformin A Suppresses Triple-Negative Breast Cancer Progression by Inducing DRP1-Mediated Mitochondrial Dysfunction and Apoptosis. Reniformin A通过诱导drp1介导的线粒体功能障碍和细胞凋亡抑制三阴性乳腺癌进展。

IF 6.3 2区医学

Phytotherapy Research Pub Date : 2025-07-27 DOI: 10.1002/ptr.70034

Yifei Guan, Lei Liu, Wei Wang, Ran Zheng, Pinghao Lin, Yalin Liu, Siyu Chen, Huiyu Zhu, Xinhui Liu, Hua Huang

{"title":"Reniformin A Suppresses Triple-Negative Breast Cancer Progression by Inducing DRP1-Mediated Mitochondrial Dysfunction and Apoptosis.","authors":"Yifei Guan, Lei Liu, Wei Wang, Ran Zheng, Pinghao Lin, Yalin Liu, Siyu Chen, Huiyu Zhu, Xinhui Liu, Hua Huang","doi":"10.1002/ptr.70034","DOIUrl":"https://doi.org/10.1002/ptr.70034","url":null,"abstract":"Reniformin A (RA) is a natural compound extracted from the medicinal herb Isodon excisoides, known for its tumor-suppressive properties in lung cancer. Yet, its effects and mechanisms of action in other cancers, such as triple-negative breast cancer (TNBC), remain unclear. This study aims to investigate the potential effects and underlying molecular mechanisms of RA in TNBC. Here, we demonstrate the significant anti-cancer activity of RA against TNBC, primarily through the induction of mitochondrial dysfunction and intrinsic apoptosis. Molecular docking and in vitro validation revealed that RA interacts directly with DRP1 at two primary binding sites. This interaction promotes the association of DRP1 with BAX, facilitating their translocation to mitochondria, where they trigger mitochondrial permeabilization, leading to the release of cytochrome c and subsequent apoptosis. Additionally, DRP1 is essential for RA-induced apoptosis; disruption of the RA-DRP1 interaction not only impeded the mitochondrial translocation of DRP1 and BAX but also significantly reduced RA's impact on mitochondrial function, apoptosis, and TNBC progression. The inhibition of the RA-DRP1 interaction also compromised the activation of apoptosis and diminished the effectiveness of RA as a chemotherapeutic agent in vivo. Collectively, these findings suggest that Reniformin A significantly inhibits TNBC by inducing DRP1/BAX-mediated apoptosis, offering a promising therapeutic strategy for TNBC treatment.","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732727","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}

引用次数: 0

Current Insights of the Potential Plant Bioactive Compounds on Modulating the mTOR Signaling Pathway in Regulating Oncological Disorders. 潜在植物生物活性化合物在调节肿瘤疾病中调控mTOR信号通路的最新研究进展。

IF 6.3 2区医学

Phytotherapy Research Pub Date : 2025-07-27 DOI: 10.1002/ptr.70051

Sonali Khanal, Manjusha Pillai, Md Shimul Bhuia, Muhammad Torequl Islam, Onkar Sharma, Rachna Verma, Eugenie Nepovimova, Kamil Kuca, Dinesh Kumar, Raihan Chowdhury

{"title":"Current Insights of the Potential Plant Bioactive Compounds on Modulating the mTOR Signaling Pathway in Regulating Oncological Disorders.","authors":"Sonali Khanal, Manjusha Pillai, Md Shimul Bhuia, Muhammad Torequl Islam, Onkar Sharma, Rachna Verma, Eugenie Nepovimova, Kamil Kuca, Dinesh Kumar, Raihan Chowdhury","doi":"10.1002/ptr.70051","DOIUrl":"https://doi.org/10.1002/ptr.70051","url":null,"abstract":"Deregulation of the mechanistic target of the rapamycin (mTOR) pathway plays an important role in cancer genesis and progression, making it an attractive target for cancer treatment. Disrupting the mTOR pathway contributes to uncontrolled cell growth, increased proliferation, and enhanced cell survival, all of which are hallmarks of cancer. The findings imply that the deregulation of the mTOR pathway in cancer provides a compelling basis for therapeutic treatments. Phytochemicals such as flavonoids and polyphenols have been shown to play a key role in suppressing different kinases implicated in PI3K/AKT/mTOR signaling cascades. A thorough study of the molecular connections between bioactive substances, mTOR signaling, and autophagy activation can lead to the creation of personalized treatments that work better and have fewer side effects. Finding out how important it is to target the mTOR pathway and how to use bioactive chemicals from plants to treat cancer are both important discoveries that could lead to more precise medicine and the development of effective cancer drugs. Finally, targeting mTOR pathways using plant-derived chemicals may be a promising therapy strategy for cancer. This review tries to summarize putative plant bioactive chemicals that act on malignancies via mTOR signaling pathways. Furthermore, the paper discusses the role of the mTOR pathway in cancer, specifically its influence on cell growth, proliferation, and survival.","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732693","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}

引用次数: 0

Embelin Mitigates the Impact of Perinatal Inflammation on Neuron Development by Inhibiting 5-Lipoxygenase-Mediated Ferroptosis. 栓塞通过抑制5-脂氧合酶介导的铁下垂减轻围产期炎症对神经元发育的影响。

IF 6.3 2区医学

Phytotherapy Research Pub Date : 2025-07-27 DOI: 10.1002/ptr.70052

Feng Zhang, Mengya Sun, Shiyi Ma, Junfang Sun, Yishi Li, Xianghong Li, Hong Jiang

{"title":"Embelin Mitigates the Impact of Perinatal Inflammation on Neuron Development by Inhibiting 5-Lipoxygenase-Mediated Ferroptosis.","authors":"Feng Zhang, Mengya Sun, Shiyi Ma, Junfang Sun, Yishi Li, Xianghong Li, Hong Jiang","doi":"10.1002/ptr.70052","DOIUrl":"https://doi.org/10.1002/ptr.70052","url":null,"abstract":"Neuronal development in newborns is often constrained by perinatal inflammation, with limited research available on the pathogenesis and treatment strategies for this condition. This study aimed to investigate the neuroprotective effects of Embelin in mitigating perinatal inflammation-induced neuronal development limitations by targeting 5-lipoxygenase (5-LOX) and reducing oxidative stress and ferroptosis. This study utilized in vivo and in vitro inflammation models to assess the therapeutic potential of Embelin, a small molecule drug from the FDA compound library. Using Autodock software and surface plasmon resonance detection technology, 5-LOX was identified as the molecular target of Embelin. Neuronal ferroptosis and oxidative stress were analyzed in rat models and PC12 cells treated with lipopolysaccharide (LPS) and Embelin. Biochemical assays, immunofluorescence staining, and western blotting were performed to quantify protein expression and oxidative stress markers. Embelin, along with the 5-LOX inhibitor Zileuton and 5-LOX mRNA silencing, significantly inhibited 5-LOX expression in neurons. Conversely, overexpressed 5-LOX promoted ferroptosis, and this effect could be inhibited by Embelin. These interventions reduced oxidative stress, suppressed ferroptosis, and promoted normal neuronal development in the cerebral cortex and hippocampus. The findings highlight Embelin's ability to specifically target and mitigate 5-LOX-induced ferroptosis, facilitating recovery from perinatal inflammation-induced neurodevelopmental deficits. Embelin demonstrates significant neuroprotective potential by inhibiting 5-LOX-mediated ferroptosis and oxidative stress, offering a promising therapeutic strategy for perinatal brain injury and related neurodevelopmental disorders.","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732726","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}

引用次数: 0

Berberine Ameliorates Atrial Remodeling and Inhibits the Atrial Fibrillation of Mice via Regulating NLRP3 Inflammasome. 小檗碱通过调节NLRP3炎性体改善小鼠心房重构和抑制心房颤动。

IF 6.3 2区医学

Phytotherapy Research Pub Date : 2025-07-26 DOI: 10.1002/ptr.70011

Na An, Fan Yang, Nian Liu, Yonghong Gao, Hongcai Shang, Yanwei Xing

{"title":"Berberine Ameliorates Atrial Remodeling and Inhibits the Atrial Fibrillation of Mice via Regulating NLRP3 Inflammasome.","authors":"Na An, Fan Yang, Nian Liu, Yonghong Gao, Hongcai Shang, Yanwei Xing","doi":"10.1002/ptr.70011","DOIUrl":"https://doi.org/10.1002/ptr.70011","url":null,"abstract":"Increased cardiomyocyte-specific activation of the NLRP3 inflammasome contributes to the development of atrial fibrillation (AF). Berberine (BBR) exhibits numerous beneficial effects on the cardiovascular system. This study investigated how the NLRP3 inflammasome regulates susceptibility to hypertension-induced AF and the effects of BBR on this susceptibility. Blood pressure was monitored in mice using a tail pressure sensor device. AF was induced by burst stimulation of the esophagus. The target proteins of BBR were screened by network pharmacology, and molecular docking was performed. The changes in atrial tissue structure were observed by pathological tissue staining and transmission electron microscopy. Western blot analysis was used for protein verification. Intracellular Ca2+ release was detected by confocal laser microscopy and the IonOptix system. We found that in angiotensin II (Ang II)-induced AF, NLRP3 inflammasome activation was inhibited, ultimately inhibiting hypertensive AF susceptibility. In a recombinant adeno-associated virus 9 (rAAV9)-NLRP3 overexpression model, BBR mitigated the increase in systolic blood pressure and the development and progression of AF by inhibiting the NLRP3 inflammasome. This study provides hitherto undocumented evidence that the NLRP3 inflammasome acts as a critical regulator in the progression of Ang II-induced AF and that BBR may serve as a viable treatment for AF by inhibiting NLRP3.","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144732692","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}

引用次数: 0

Natural Products in Regulating Mitophagy for the Intervention of Atherosclerosis and Its Risk Factors: Mechanisms and Therapeutic Potential. 调节线粒体自噬干预动脉粥样硬化及其危险因素的天然产物：机制和治疗潜力。

IF 6.1 2区医学

Phytotherapy Research Pub Date : 2025-07-22 DOI: 10.1002/ptr.70041

Yu-Han Li, Hao Ma, Ying-Rui Wang, Si-Xiang Zhang, You-Min Zhao, Zheng Liu

{"title":"Natural Products in Regulating Mitophagy for the Intervention of Atherosclerosis and Its Risk Factors: Mechanisms and Therapeutic Potential.","authors":"Yu-Han Li, Hao Ma, Ying-Rui Wang, Si-Xiang Zhang, You-Min Zhao, Zheng Liu","doi":"10.1002/ptr.70041","DOIUrl":"https://doi.org/10.1002/ptr.70041","url":null,"abstract":"Atherosclerosis (AS) is a chronic systemic disease that poses a significant and escalating global challenge. The pathological process of AS involves multiple aspects. In addition to lipid-lowering therapy, therapeutic strategies such as anti-inflammatory and immunotherapy have been proposed, and attention has been paid to the intervention of its risk factors. However, the available drugs are still limited. Therefore, there is an urgent need to discover new pharmacological targets and drugs. Mitophagy is closely associated with AS and its risk factors, and it represents an important breakthrough in the intervention of AS and its risk factors. Natural products (NPs), with multiple pharmacological activities and lower toxicity, have caught attention as the new force in the treatment of AS and its risk factors. This review discusses the mechanisms and therapeutic potential of NPs in regulating mitophagy to alleviate AS and intervene in its risk factors. It also introduces the application prospects of the NPs, with the expectation of contributing to the treatment of AS and the development of innovative drugs.","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144691221","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}

引用次数: 0

l-Theanine Improves Learning and Memory Through Attenuation of NOX4-Mediated Ferroptosis in Hippocampal Neurons of Sleep-Deprived Mice. l-茶氨酸通过抑制睡眠剥夺小鼠海马神经元nox4介导的铁下垂改善学习和记忆。

IF 6.1 2区医学

Phytotherapy Research Pub Date : 2025-07-19 DOI: 10.1002/ptr.70048

Xuanxuan Huang, Xinglong Lu, Zhenghua Wu, Hongfei Wu, Zhongwen Xie, Yin Cao

{"title":"l-Theanine Improves Learning and Memory Through Attenuation of NOX4-Mediated Ferroptosis in Hippocampal Neurons of Sleep-Deprived Mice.","authors":"Xuanxuan Huang, Xinglong Lu, Zhenghua Wu, Hongfei Wu, Zhongwen Xie, Yin Cao","doi":"10.1002/ptr.70048","DOIUrl":"https://doi.org/10.1002/ptr.70048","url":null,"abstract":"Sleep deprivation (SD) can negatively affect the central nervous system owing to its detrimental effects on learning and memory. l-theanine, known for its antioxidative properties, can confer neuroprotection by enhancing learning and memory. Here, we explored whether l-theanine could improve learning and memory by inhibiting the NOX4-mediated ferroptosis in hippocampal neurons caused by SD. The Morris water maze (MWM) was employed to assess learning and memory ability. MDA, SOD, GSH, LDH, and Fe2+ levels were measured using their specific assay kits. The degree of damage in hippocampal neurons was examined by Nissl staining. The process of ferroptosis in the hippocampus of SD mice and HT22 cells was analyzed using transmission electron microscopy (TEM), immunohistochemistry, flow cytometry, and Western blotting assays. l-Theanine treatment significantly increased the frequency of mice crossing the platform. Moreover, it conferred protection on hippocampal neurons and mitochondria in SD mice. Furthermore, l-theanine mitigated Erastin-induced oxidative stress and ferroptosis in HT22 cells. In addition, it reversed the abnormal expression of proteins including PSD-95, SYN, NOX4, TFRC, ACSL4, Nrf2, Keap1, SLC7A11, P53, HO-1, NQO1, FTH1, and GPX4 in the hippocampus of SD mice and in the HT22 cells induced by Erastin. Moreover, the neuroprotection of l-theanine was reversed by the GLX351322 agent. l-Theanine treatment inhibited hippocampal ferroptosis by attenuating NOX4, suggesting that it can be used to mitigate the adverse effects of SD.","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144668184","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}

引用次数: 0

Discovery of Baicalein as a Novel Ubiquitin-Specific Protease 21 Inhibitor for the Treatment of Hepatocellular Carcinoma. 黄芩素作为治疗肝癌的新型泛素特异性蛋白酶21抑制剂的发现。

IF 6.1 2区医学

Phytotherapy Research Pub Date : 2025-07-17 DOI: 10.1002/ptr.70022

Huijun Jia, Zhuoyue Zhao, Chen Su, Jiapeng Du, Shuaizhou Yang, Jiankun Song, Xu Han, Fang Yu, Zhaolin Sun, Peng Chu

{"title":"Discovery of Baicalein as a Novel Ubiquitin-Specific Protease 21 Inhibitor for the Treatment of Hepatocellular Carcinoma.","authors":"Huijun Jia, Zhuoyue Zhao, Chen Su, Jiapeng Du, Shuaizhou Yang, Jiankun Song, Xu Han, Fang Yu, Zhaolin Sun, Peng Chu","doi":"10.1002/ptr.70022","DOIUrl":"https://doi.org/10.1002/ptr.70022","url":null,"abstract":"Ubiquitin-specific protease 21 (USP21) is amplified and overexpressed in hepatocellular carcinoma (HCC), correlating with poor prognosis, suggesting USP21 inhibition as a therapeutic strategy. This study aims to identify novel USP21 inhibitors and elucidate their molecular mechanisms in HCC treatment. USP21 inhibitors were identified via structure-guided drug discovery, enzymatic assays, and bio-layer interferometry. Functional validation included proliferation, migration, colony formation, and apoptosis assays. USP21-mediated hypoxia-inducible factor-1α (HIF-1α) regulation was assessed using qRT-PCR, co-immunoprecipitation, and deubiquitination assays. In vivo efficacy was evaluated in murine allograft models, with binding modes resolved via molecular dynamics simulations and binding free energy calculations. Screening 4000 natural compounds identified Baicalein and Hypericin as USP21 inhibitors (50% inhibitory concentration: 2.45 and 17.68 μM, respectively). Baicalein suppressed HCC proliferation, colony formation, and migration while inducing apoptosis. Mechanistically, USP21 directly stabilized HIF-1α via deubiquitination, which Baicalein disrupted by blocking the USP21-HIF-1α interaction, promoting HIF-1α degradation. In vivo, Baicalein inhibited tumor growth and enhanced intratumoral T-cell infiltration. Structural analyses identified Gln300, His510, and Gly517 as critical residues for USP21-inhibitor binding. Baicalein emerges as a dual-functional USP21 inhibitor that destabilizes HIF-1α and reprograms the tumor immune microenvironment. The Gln300/His510/Gly517 binding motif provides a structural blueprint for advanced USP21-targeted drug design, establishing USP21 inhibition as a promising therapeutic strategy for HCC.","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144659894","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}

引用次数: 0