Pub Date : 2026-04-01Epub Date: 2026-02-17DOI: 10.1016/j.phymed.2026.157979
Xiao Chu, Hui Zheng, Jingyi Sun, Ke Liu, Yang Shao, Siyuan Han, Liangge Zhao, Ruoshi Dou, Xingen Jia, Jiayao Huang, Meng Liu, Ziliang Zhang, Tao Li, Hao Li, Zhiping Guo, Guoguo Jin
Background: Doxorubicin-induced cardiotoxicity (DIC) is a severe dose-limiting complication of chemotherapy. Acteoside (ACT), a bioactive phenylethanoid glycoside naturally isolated from various medicinal plants such as Plantago lanceolata and Acanthus ilicifolius, exhibits diverse pharmacological activities. However, its specific role and molecular targets in DIC remain largely unreported.
Objective: To evaluate the cardioprotective efficacy of ACT in DIC and identify its direct molecular targets and cardiac protection mechanisms.
Methods: Proteomic profiling of DOX-treated hearts and AAV9-mediated cardiac-specific silencing were integrated to identify and validate glutamine synthetase (GS) as a pivotal pathological driver of DIC. Subsequently, structure-based virtual screening of phytochemicals was employed to identify ACT as a potent GS inhibitor. The ACT-GS interaction was confirmed via molecular docking, pull-down, and cellular thermal shift assays. Functional and mechanistic validations were conducted using H9C2/HL-1 cells and C57BL/6 J mouse models.
Results: Proteomics revealed significant myocardial GS upregulation and glutamate metabolic remodeling in DIC. ACT was identified as a direct inhibitor that specifically binds to GS. Mechanistically, ACT-mediated GS inhibition prevented pathological glutamate depletion and restored the GLU-GSH-GPX4 antioxidant axis, thereby suppressing lipid peroxidation and ferroptosis both in vitro and in vivo. Consequently, ACT administration significantly attenuated DOX-induced cardiac dysfunction, fibrosis, and myocardial atrophy, effectively recapitulating the protective effects observed with genetic GS knockdown.
Conclusion: ACT acts as a potent natural GS inhibitor that alleviates DIC by suppressing ferroptosis. This study establishes ACT as a promising natural lead compound for the management of DIC.
{"title":"Acteoside targeting glutamine synthetase ameliorates doxorubicin-induced cardiotoxicity by inhibiting ferroptosis.","authors":"Xiao Chu, Hui Zheng, Jingyi Sun, Ke Liu, Yang Shao, Siyuan Han, Liangge Zhao, Ruoshi Dou, Xingen Jia, Jiayao Huang, Meng Liu, Ziliang Zhang, Tao Li, Hao Li, Zhiping Guo, Guoguo Jin","doi":"10.1016/j.phymed.2026.157979","DOIUrl":"10.1016/j.phymed.2026.157979","url":null,"abstract":"<p><strong>Background: </strong>Doxorubicin-induced cardiotoxicity (DIC) is a severe dose-limiting complication of chemotherapy. Acteoside (ACT), a bioactive phenylethanoid glycoside naturally isolated from various medicinal plants such as Plantago lanceolata and Acanthus ilicifolius, exhibits diverse pharmacological activities. However, its specific role and molecular targets in DIC remain largely unreported.</p><p><strong>Objective: </strong>To evaluate the cardioprotective efficacy of ACT in DIC and identify its direct molecular targets and cardiac protection mechanisms.</p><p><strong>Methods: </strong>Proteomic profiling of DOX-treated hearts and AAV9-mediated cardiac-specific silencing were integrated to identify and validate glutamine synthetase (GS) as a pivotal pathological driver of DIC. Subsequently, structure-based virtual screening of phytochemicals was employed to identify ACT as a potent GS inhibitor. The ACT-GS interaction was confirmed via molecular docking, pull-down, and cellular thermal shift assays. Functional and mechanistic validations were conducted using H9C2/HL-1 cells and C57BL/6 J mouse models.</p><p><strong>Results: </strong>Proteomics revealed significant myocardial GS upregulation and glutamate metabolic remodeling in DIC. ACT was identified as a direct inhibitor that specifically binds to GS. Mechanistically, ACT-mediated GS inhibition prevented pathological glutamate depletion and restored the GLU-GSH-GPX4 antioxidant axis, thereby suppressing lipid peroxidation and ferroptosis both in vitro and in vivo. Consequently, ACT administration significantly attenuated DOX-induced cardiac dysfunction, fibrosis, and myocardial atrophy, effectively recapitulating the protective effects observed with genetic GS knockdown.</p><p><strong>Conclusion: </strong>ACT acts as a potent natural GS inhibitor that alleviates DIC by suppressing ferroptosis. This study establishes ACT as a promising natural lead compound for the management of DIC.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"153 ","pages":"157979"},"PeriodicalIF":8.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147318096","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}
Pub Date : 2026-04-01Epub Date: 2026-02-22DOI: 10.1016/j.phymed.2026.157996
Qi Xue, Yueqiang Gu, Ran Qin, Zijia Chen, Jie Li, Mingying Li, Yiping Li, Changhao Li, Weicheng Gao, Baohua Liu, Renlei Yang
Background: Age-related knee osteoarthritis (OA) arises from cumulative oxidative damage, chondrocyte senescence and extracellular matrix loss; yet safe and effective disease‑modifying interventions for aging‑associated OA are lacking. Pyrroloquinoline quinone (PQQ; molecular formula C14H6N2O8) is a naturally bioactive compound that has been reported to activate nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor that regulates antioxidant and cytoprotective gene expression. However, its effects on age-related OA and the underlying mechanisms remain unclear.
Methods: Twelve‑month‑old mice received dietary PQQ (4 mg/kg feed) for 12 months and joint pathology was assessed by Safranin O-Fast Green staining, osteoarthritis research society international (OARSI) grading, osteophyte and synovitis scoring, and micro‑computed tomography (μCT). Oxidative damage, senescence and extracellular matrix markers were analyzed. Human and mouse chondrocytes and cartilage explants were treated with interleukin-1β (IL‑1β) to model OA in vitro; effects of PQQ on oxidative stress, proliferation, senescence and matrix proteins were measured. Nrf2 signaling activation was examined. Mechanistic assays investigated how Nrf2 regulates the insulin‑like growth factor 1 receptor (IGF1R). Nrf2 or IGF1R loss‑of‑function evaluated pathway dependence.
Results: Long‑term dietary PQQ markedly reduced spontaneous, age‑related OA in mice. It lowered OARSI scores and reduced osteophyte formation and synovitis, while preserving cartilage and subchondral bone structure. PQQ also decreased oxidative DNA damage in cartilage, reduced senescence markers and senescence‑associated secretory phenotype (SASP) factors, and restored Lamin B1. In addition, it reduced matrix metalloproteinase‑13 (MMP13) and maintained COL2A1 expression. In IL‑1β‑challenged human chondrocytes and explants, PQQ suppressed oxidative stress, rescued proliferation, diminished senescence and prevented matrix degradation. PQQ enhanced Nrf2 nuclear accumulation, antioxidant response element (ARE) activity and antioxidant genes expression. Mechanistic assays identified IGF1R as a direct Nrf2 target; IGF1R knockdown blocked PQQ‑induced extracellular signal‑regulated kinase (ERK) signaling and COL2A1 upregulation. PQQ failed to protect Nrf2‑deficient chondrocytes and joints, demonstrating Nrf2 dependence.
Conclusion: PQQ mitigates age‑related OA by activating Nrf2‑mediated antioxidant/anti‑senescence responses and transcriptionally upregulating IGF1R to support matrix anabolism. The PQQ-Nrf2-IGF1R axis is a promising therapeutic target for preventing or slowing age‑related OA progression.
{"title":"Pyrroloquinoline quinone alleviates age-related osteoarthritis via nuclear factor erythroid 2-related factor 2-mediated stress response and insulin-like growth factor 1 receptor upregulation.","authors":"Qi Xue, Yueqiang Gu, Ran Qin, Zijia Chen, Jie Li, Mingying Li, Yiping Li, Changhao Li, Weicheng Gao, Baohua Liu, Renlei Yang","doi":"10.1016/j.phymed.2026.157996","DOIUrl":"10.1016/j.phymed.2026.157996","url":null,"abstract":"<p><strong>Background: </strong>Age-related knee osteoarthritis (OA) arises from cumulative oxidative damage, chondrocyte senescence and extracellular matrix loss; yet safe and effective disease‑modifying interventions for aging‑associated OA are lacking. Pyrroloquinoline quinone (PQQ; molecular formula C<sub>14</sub>H<sub>6</sub>N<sub>2</sub>O<sub>8</sub>) is a naturally bioactive compound that has been reported to activate nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor that regulates antioxidant and cytoprotective gene expression. However, its effects on age-related OA and the underlying mechanisms remain unclear.</p><p><strong>Methods: </strong>Twelve‑month‑old mice received dietary PQQ (4 mg/kg feed) for 12 months and joint pathology was assessed by Safranin O-Fast Green staining, osteoarthritis research society international (OARSI) grading, osteophyte and synovitis scoring, and micro‑computed tomography (μCT). Oxidative damage, senescence and extracellular matrix markers were analyzed. Human and mouse chondrocytes and cartilage explants were treated with interleukin-1β (IL‑1β) to model OA in vitro; effects of PQQ on oxidative stress, proliferation, senescence and matrix proteins were measured. Nrf2 signaling activation was examined. Mechanistic assays investigated how Nrf2 regulates the insulin‑like growth factor 1 receptor (IGF1R). Nrf2 or IGF1R loss‑of‑function evaluated pathway dependence.</p><p><strong>Results: </strong>Long‑term dietary PQQ markedly reduced spontaneous, age‑related OA in mice. It lowered OARSI scores and reduced osteophyte formation and synovitis, while preserving cartilage and subchondral bone structure. PQQ also decreased oxidative DNA damage in cartilage, reduced senescence markers and senescence‑associated secretory phenotype (SASP) factors, and restored Lamin B1. In addition, it reduced matrix metalloproteinase‑13 (MMP13) and maintained COL2A1 expression. In IL‑1β‑challenged human chondrocytes and explants, PQQ suppressed oxidative stress, rescued proliferation, diminished senescence and prevented matrix degradation. PQQ enhanced Nrf2 nuclear accumulation, antioxidant response element (ARE) activity and antioxidant genes expression. Mechanistic assays identified IGF1R as a direct Nrf2 target; IGF1R knockdown blocked PQQ‑induced extracellular signal‑regulated kinase (ERK) signaling and COL2A1 upregulation. PQQ failed to protect Nrf2‑deficient chondrocytes and joints, demonstrating Nrf2 dependence.</p><p><strong>Conclusion: </strong>PQQ mitigates age‑related OA by activating Nrf2‑mediated antioxidant/anti‑senescence responses and transcriptionally upregulating IGF1R to support matrix anabolism. The PQQ-Nrf2-IGF1R axis is a promising therapeutic target for preventing or slowing age‑related OA progression.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"153 ","pages":"157996"},"PeriodicalIF":8.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147322201","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}
Background: Gut microbiota dysbiosis is implicated in rheumatoid arthritis (RA). While Lycium barbarum polysaccharide-enriched extract (LBP) is known for its anti-inflammatory and immunoregulatory effects, the precise microbial drivers and underlying mechanisms, including their connection to the T follicular helper (Tfh) cell/B cell axis, remain poorly defined.
Purpose: The aim of this research is to investigate changes in the gut microbiota of RA patients and CIA rats, and to evaluate whether LBP improves RA by modulating the gut microbiota.
Method: Gut microbiota composition was assessed via 16S rRNA gene sequencing in both RA patients and CIA rats. To investigate the mechanisms underlying the therapeutic effect of LBP, flow cytometry, ELISA, and hematoxylin-eosin (HE) staining were employed.
Results: In RA patients, gut microbiota α-diversity was significantly reduced, coupled with decreased levels of Ligilactobacillus and Escherichia-Shigella and an increase in Blautia. In the CIA rat model, LBP treatment counteracted the observed microbiota shifts by increasing the diminished abundances of Ligilactobacillus and Limosilactobacillus and reducing the elevated abundance of Blautia. Specifically, LBP reduced the proportions of splenic Tfh and B cells and lowered serum levels of IgG, IL-6, and IL-21. It also diminished inflammatory infiltration and synovial hyperplasia in joint tissues and repaired colonic crypt architecture.
Conclusion: Dysbiosis of the gut microbiota and abnormal activation of Tfh cells may play an essential role in the development and progression of RA. In both human patients and the CIA rats model, Ligilactobacillus and Blautia have been associated with RA pathological processes. LBP may suppress the excessive proliferation of Tfh cells and the subsequent abnormal differentiation of B cells. It is noteworthy that alterations in these key bacterial genera may be linked to the regulation of Tfh cell overactivation and aberrant humoral immune responses.
{"title":"Lycium barbarum Polysaccharides-enriched extract Ameliorate Rheumatoid Arthritis via Gut microbiota-mediated regulation of the Tfh/B cell axis.","authors":"Chunlei Jiang, Danyan Chen, Jing Li, Xiaoqi Yue, Shuo Wang, Gan Cao, Shuhong Chi, Yanli Zhang","doi":"10.1016/j.phymed.2026.158019","DOIUrl":"10.1016/j.phymed.2026.158019","url":null,"abstract":"<p><strong>Background: </strong>Gut microbiota dysbiosis is implicated in rheumatoid arthritis (RA). While Lycium barbarum polysaccharide-enriched extract (LBP) is known for its anti-inflammatory and immunoregulatory effects, the precise microbial drivers and underlying mechanisms, including their connection to the T follicular helper (Tfh) cell/B cell axis, remain poorly defined.</p><p><strong>Purpose: </strong>The aim of this research is to investigate changes in the gut microbiota of RA patients and CIA rats, and to evaluate whether LBP improves RA by modulating the gut microbiota.</p><p><strong>Method: </strong>Gut microbiota composition was assessed via 16S rRNA gene sequencing in both RA patients and CIA rats. To investigate the mechanisms underlying the therapeutic effect of LBP, flow cytometry, ELISA, and hematoxylin-eosin (HE) staining were employed.</p><p><strong>Results: </strong>In RA patients, gut microbiota α-diversity was significantly reduced, coupled with decreased levels of Ligilactobacillus and Escherichia-Shigella and an increase in Blautia. In the CIA rat model, LBP treatment counteracted the observed microbiota shifts by increasing the diminished abundances of Ligilactobacillus and Limosilactobacillus and reducing the elevated abundance of Blautia. Specifically, LBP reduced the proportions of splenic Tfh and B cells and lowered serum levels of IgG, IL-6, and IL-21. It also diminished inflammatory infiltration and synovial hyperplasia in joint tissues and repaired colonic crypt architecture.</p><p><strong>Conclusion: </strong>Dysbiosis of the gut microbiota and abnormal activation of Tfh cells may play an essential role in the development and progression of RA. In both human patients and the CIA rats model, Ligilactobacillus and Blautia have been associated with RA pathological processes. LBP may suppress the excessive proliferation of Tfh cells and the subsequent abnormal differentiation of B cells. It is noteworthy that alterations in these key bacterial genera may be linked to the regulation of Tfh cell overactivation and aberrant humoral immune responses.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"153 ","pages":"158019"},"PeriodicalIF":8.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147326818","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}
Pub Date : 2026-04-01Epub Date: 2026-02-02DOI: 10.1016/j.phymed.2026.157917
Jieli Pan , Jinjun Ji , Xingpan Xin , Yihong Gan , Zixin Huang , Jing Chen , Ying Li , Jie Bao , Yujun Tang , Chengping Wen , Li Xu
Background
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.
Purpose
This study aimed to investigate whether genistein, a phytoestrogen with selective affinity for ERβ, can modulate the ERβ–STAT3 axis to attenuate lupus nephritis.
Methods
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.
Results
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.
Conclusion
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.
{"title":"Genistein ameliorates lupus nephritis via enhancing ERβ-mediated inhibition of STAT3-driven inflammation","authors":"Jieli Pan , Jinjun Ji , Xingpan Xin , Yihong Gan , Zixin Huang , Jing Chen , Ying Li , Jie Bao , Yujun Tang , Chengping Wen , 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":"2026-04-01","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}
Pub Date : 2026-04-01Epub Date: 2026-01-16DOI: 10.1016/j.phymed.2026.157839
Li-Yuan Lin , Heng-Zhen Li , Xiang-Qian Liu , Si Xiong , Man-Mei Li , He-Yun Zhang , Chui-Wen Qian , Zhong Liu
Background
Isodeoxyelephantopin (IDET) is a sesquiterpene lactone isolated from traditional herb Elephantopus scaber, which is known for its anti-inflammatory activities. While our previous study demonstrated that IDET inhibits NLRP3 expression in an acute peritonitis model, its therapeutic potential in chronic inflammatory diseases such as ulcerative colitis (UC), as well as the underlying mechanisms involving inflammasome signaling, have not yet been fully elucidated.
Purpose
This research was designed to explain the protective capacity of IDET in UC and to clarify how IDET modulates IL-1β-mediated inflammatory responses through the TXNIP/NLRP3 signaling pathway, by integrating in vitro and in vivo experimental systems.
Results
IDET significantly reduced dextran sulfate sodium (DSS)-induced colitis in mice, improving disease scores, reducing inflammation, and preserving colon histology. Mechanistically, IDET exerted a multi-tiered suppression of the inflammasome pathway, which suppresses IL-1β-driven inflammation. Firstly, it disrupted the upstream priming signal by downregulating NLRP3 expression through NF-κB signaling pathway. Secondly, it inhibited inflammasome assembly, as evidenced by reduced ASC oligomerization and NLRP3-ASC interaction. Consequently, IDET reduced the cleavage of pro-caspase-1 and pro-IL-1β, resulting in an approximately 4-fold reduction in mature IL-1β secretion. A key finding was that IDET interfered with the activation signal by attenuating the TXNIP-NLRP3 interaction, according to immunoprecipitation and molecular docking results.
Conclusions
Extending our previous findings on its anti-acute inflammatory activity, this study demonstrates that IDET alleviates experimental ulcerative colitis by targeting multiple stages of NLRP3 inflammasome activation. The results highlight the translational potential of IDET, a natural compound, for treating chronic intestinal inflammation.
{"title":"Isodeoxyelephantopin mitigates DSS-induced ulcerative colitis by suppressing IL-1β-driven inflammation via the TXNIP/NLRP3 axis","authors":"Li-Yuan Lin , Heng-Zhen Li , Xiang-Qian Liu , Si Xiong , Man-Mei Li , He-Yun Zhang , Chui-Wen Qian , Zhong Liu","doi":"10.1016/j.phymed.2026.157839","DOIUrl":"10.1016/j.phymed.2026.157839","url":null,"abstract":"<div><h3>Background</h3><div>Isodeoxyelephantopin (IDET) is a sesquiterpene lactone isolated from traditional herb <em>Elephantopus scaber</em>, which is known for its anti-inflammatory activities. While our previous study demonstrated that IDET inhibits NLRP3 expression in an acute peritonitis model, its therapeutic potential in chronic inflammatory diseases such as ulcerative colitis (UC), as well as the underlying mechanisms involving inflammasome signaling, have not yet been fully elucidated.</div></div><div><h3>Purpose</h3><div>This research was designed to explain the protective capacity of IDET in UC and to clarify how IDET modulates IL-1β-mediated inflammatory responses through the TXNIP/NLRP3 signaling pathway, by integrating <em>in vitro</em> and <em>in vivo</em> experimental systems.</div></div><div><h3>Results</h3><div>IDET significantly reduced dextran sulfate sodium (DSS)-induced colitis in mice, improving disease scores, reducing inflammation, and preserving colon histology. Mechanistically, IDET exerted a multi-tiered suppression of the inflammasome pathway, which suppresses IL-1β-driven inflammation. Firstly, it disrupted the upstream priming signal by downregulating NLRP3 expression through NF-κB signaling pathway. Secondly, it inhibited inflammasome assembly, as evidenced by reduced ASC oligomerization and NLRP3-ASC interaction. Consequently, IDET reduced the cleavage of pro-caspase-1 and pro-IL-1β, resulting in an approximately 4-fold reduction in mature IL-1β secretion. A key finding was that IDET interfered with the activation signal by attenuating the TXNIP-NLRP3 interaction, according to immunoprecipitation and molecular docking results.</div></div><div><h3>Conclusions</h3><div>Extending our previous findings on its anti-acute inflammatory activity, this study demonstrates that IDET alleviates experimental ulcerative colitis by targeting multiple stages of NLRP3 inflammasome activation. The results highlight the translational potential of IDET, a natural compound, for treating chronic intestinal inflammation.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"153 ","pages":"Article 157839"},"PeriodicalIF":8.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146143253","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}
Pub Date : 2026-04-01Epub Date: 2026-01-28DOI: 10.1016/j.phymed.2026.157893
Cheng Tang , Jingxian Yu , Dong Sheng , Yong Gu , Donglong Xia , Kuibing Lan , Yajun Li , Yunshang Yang , Chengcheng Feng , Yu Gong , Long Xiao , Zhirong Wang
Objectives
Dysregulated mitophagy coupled with osteoclast activation orchestrates the development and progression of osteoporosis.Although albiflorin (ALB) exhibits bone-protective effects through anti-inflammatory and antioxidant activities, its precise mechanism—particularly regarding mitochondrial regulation—remains unknown. This study therefore investigates ALB as a novel osteoclast inhibitor by examining its molecular mechanism in regulating mitophagy via the Rap1a/ERK signaling pathway.
Materials and Methods
ALB was evaluated using murine models of postmenopausal osteoporosis. Key methodologies included RNA sequencing (RNA-seq) for gene expression pathway analysis, transmission electron microscopy (TEM) for visualization of mitochondrial and autophagic structures, MitoTracker/LysoTracker co-staining for assessment of mitophagy, and Western blotting for protein signaling validation. The impact of ALB on osteoclast differentiation and the prevention of bone loss was evaluated in both laboratory and live animal studies..
Results
ALB significantly inhibited osteoclastogenesis and osteoclast differentiation, thereby effectively reducing osteoporosis in murine models. RNA-seq analysis revealed that ALB modulated mitophagy by regulating the expression of Rap1a and components of the ERK signaling pathway. Validation through TEM demonstrated suppressed mitochondrial autophagy, while MitoTracker/LysoTracker co-staining confirmed a reduction in mitophagy. Furthermore, Western blot analysis showed that ALB inhibited osteoclast activation via the Rap1a/ERK signaling axis.
Conclusion
ALB mitigates postmenopausal osteoporosis by suppressing osteoclast activation through Rap1a/ERK-dependent inhibition of mitophagy. These findings identify ALB as a promising therapeutic strategy for osteoporosis, addressing the need for safer long-term treatment options.
{"title":"Albiflorin alleviates osteoporosis through suppression of osteoclast mitophagy via the Rap1a/ERK signaling pathway","authors":"Cheng Tang , Jingxian Yu , Dong Sheng , Yong Gu , Donglong Xia , Kuibing Lan , Yajun Li , Yunshang Yang , Chengcheng Feng , Yu Gong , Long Xiao , Zhirong Wang","doi":"10.1016/j.phymed.2026.157893","DOIUrl":"10.1016/j.phymed.2026.157893","url":null,"abstract":"<div><h3>Objectives</h3><div>Dysregulated mitophagy coupled with osteoclast activation orchestrates the development and progression of osteoporosis.Although albiflorin (ALB) exhibits bone-protective effects through anti-inflammatory and antioxidant activities, its precise mechanism—particularly regarding mitochondrial regulation—remains unknown. This study therefore investigates ALB as a novel osteoclast inhibitor by examining its molecular mechanism in regulating mitophagy via the Rap1a/ERK signaling pathway.</div></div><div><h3>Materials and Methods</h3><div>ALB was evaluated using murine models of postmenopausal osteoporosis. Key methodologies included RNA sequencing (RNA-seq) for gene expression pathway analysis, transmission electron microscopy (TEM) for visualization of mitochondrial and autophagic structures, MitoTracker/LysoTracker co-staining for assessment of mitophagy, and Western blotting for protein signaling validation. The impact of ALB on osteoclast differentiation and the prevention of bone loss was evaluated in both laboratory and live animal studies..</div></div><div><h3>Results</h3><div>ALB significantly inhibited osteoclastogenesis and osteoclast differentiation, thereby effectively reducing osteoporosis in murine models. RNA-seq analysis revealed that ALB modulated mitophagy by regulating the expression of Rap1a and components of the ERK signaling pathway. Validation through TEM demonstrated suppressed mitochondrial autophagy, while MitoTracker/LysoTracker co-staining confirmed a reduction in mitophagy. Furthermore, Western blot analysis showed that ALB inhibited osteoclast activation via the Rap1a/ERK signaling axis.</div></div><div><h3>Conclusion</h3><div>ALB mitigates postmenopausal osteoporosis by suppressing osteoclast activation through Rap1a/ERK-dependent inhibition of mitophagy. These findings identify ALB as a promising therapeutic strategy for osteoporosis, addressing the need for safer long-term treatment options.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"153 ","pages":"Article 157893"},"PeriodicalIF":8.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146166391","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}
Growing cognitive health interest fuels 8.3% market growth. Bacopa monnieri Wettst. (Brahmi) and Ginkgo biloba 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.
Methods
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).
Results
Twenty-nine RCTs (n = 2107) were included. High-dose Brahmi (≥600 mg/day) significantly improved working memory compared to low-dose Brahmi (300 to <600 mg/day), high-dose Ginkgo (≥240 mg/day), low-dose Ginkgo (60 to <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.
Conclusion
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.
Other
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).
背景：日益增长的认知健康兴趣推动了8.3%的市场增长。假马齿苋。（Brahmi）和银杏（Ginkgo biloba L.）是研究最多的天然益智药，但它们的效果还没有直接比较。本研究旨在通过网络荟萃分析来评估和比较它们在健康成人中的疗效。方法：检索2024年11月出版的PubMed、EMBASE、Cochrane CENTRAL和EBSCO开放论文。随机对照试验（rct）纳入健康成人接受婆罗门或银杏提取物和报告的认知结果。使用Cochrane Risk of bias version 2评估偏倚风险。在随机效应模型下，采用95%置信区间（CI）的标准化平均差异（SMDs）分析认知结果。采用累积排序曲线（SUCRA）下的曲面对干预措施进行排序。结果：共纳入29项rct （n = 2107）。高剂量的Brahmi（≥600毫克/天）与低剂量的Brahmi（300毫克/天）相比，显著改善了工作记忆。结论：与银杏相比，在健康成年人中，Brahmi，特别是高剂量配方，显示出了作为认知增强剂的希望。然而，缺乏直接比较可能会限制这一证据的强度。其他：作者感谢皇家金禧博士计划（RGJ-Ph.D.）的资助。泰国研究基金（TRF） （N41A670299）。本研究已在PROSPERO注册（CRD420251034900）。
{"title":"Comparative effects of Bacopa monnieri and Ginkgo biloba on cognitive functions: A systematic review and network meta-analysis","authors":"Pailada Tiemtad , Kornkanok Ingkaninan , Prapapan Temkitthawon , Phiyanuch Thimkorn , Natnicha Rattanachaisit , Thanasak Teaktong , 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 <600 mg/day), high-dose Ginkgo (≥240 mg/day), low-dose Ginkgo (60 to <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":"2026-04-01","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}
Pub Date : 2026-04-01Epub Date: 2026-01-30DOI: 10.1016/j.phymed.2026.157913
Rong Xue , Yi-Chen Dong , Xia Wang , Shen-Zhi Liang , Xia-Lian Fan , Guang-Ming Wan
Background
Choroidal neovascularization (CNV) is a leading cause of central vision impairment with limited treatment options. Ethyl ferulate is a natural compound with antioxidant and anti-angiogenic properties; however, its application for treating CNV and the underlying mechanisms remain largely unexplored.
Purpose
The aim of this study was to evaluate the therapeutic effects of ethyl ferulate on CNV and elucidate the underlying molecular mechanisms involved.
Methods
A laser-induced CNV mouse model received intravitreal injection of ethyl ferulate. Ocular evaluations included fundus fluorescein angiography, optical coherence tomography, and H&E staining. Mechanistic studies in retinal pigment epithelial (RPE) cells employed western blotting, co-immunoprecipitation, surface plasmon resonance, molecular docking, RT-qPCR, and chromatin immunoprecipitation, while anti-angiogenic activity in human umbilical vein endothelial cells utilized proliferation, migration, and tube formation assays.
Results
Intravitreal injection of ethyl ferulate significantly suppressed neovascularization in mice with laser-induced CNV in vivo, and conditioned medium from ethyl ferulate-treated ARPE-19 cells inhibited the proliferation, migration, and tube formation of endothelial cells in vitro. Mechanistically, the proteasome 26S subunit non-ATPase 14 (PSMD14) bound to and stabilized Keap1. Ethyl ferulate, however, reduced the expression of the deubiquitinase PSMD14, promoting Keap1 ubiquitination and degradation, which activated the Nrf2 antioxidant pathway. Furthermore, enrichment of the transcription factor MAZ was detected in the promoter region of PSMD14, which enhanced PSMD14 transcription. Ethyl ferulate treatment downregulated MAZ expression, thereby reducing PSMD14 transcription.
Conclusion
Inhibition of the deubiquitinase PSMD14 to activate the Keap1/Nrf2 pathway may represent a mechanism by which ethyl ferulate suppresses CNV, supporting its promising prospects as a potential therapeutic candidate for CNV.
{"title":"Ethyl ferulate suppresses choroidal neovascularization by accelerating Keap1 degradation through the inhibition of PSMD14-mediated deubiquitination","authors":"Rong Xue , Yi-Chen Dong , Xia Wang , Shen-Zhi Liang , Xia-Lian Fan , Guang-Ming Wan","doi":"10.1016/j.phymed.2026.157913","DOIUrl":"10.1016/j.phymed.2026.157913","url":null,"abstract":"<div><h3>Background</h3><div>Choroidal neovascularization (CNV) is a leading cause of central vision impairment with limited treatment options. Ethyl ferulate is a natural compound with antioxidant and anti-angiogenic properties; however, its application for treating CNV and the underlying mechanisms remain largely unexplored.</div></div><div><h3>Purpose</h3><div>The aim of this study was to evaluate the therapeutic effects of ethyl ferulate on CNV and elucidate the underlying molecular mechanisms involved.</div></div><div><h3>Methods</h3><div>A laser-induced CNV mouse model received intravitreal injection of ethyl ferulate. Ocular evaluations included fundus fluorescein angiography, optical coherence tomography, and H&E staining. Mechanistic studies in retinal pigment epithelial (RPE) cells employed western blotting, co-immunoprecipitation, surface plasmon resonance, molecular docking, RT-qPCR, and chromatin immunoprecipitation, while anti-angiogenic activity in human umbilical vein endothelial cells utilized proliferation, migration, and tube formation assays.</div></div><div><h3>Results</h3><div>Intravitreal injection of ethyl ferulate significantly suppressed neovascularization in mice with laser-induced CNV <em>in vivo</em>, and conditioned medium from ethyl ferulate-treated ARPE-19 cells inhibited the proliferation, migration, and tube formation of endothelial cells <em>in vitro</em>. Mechanistically, the proteasome 26S subunit non-ATPase 14 (PSMD14) bound to and stabilized Keap1. Ethyl ferulate, however, reduced the expression of the deubiquitinase PSMD14, promoting Keap1 ubiquitination and degradation, which activated the Nrf2 antioxidant pathway. Furthermore, enrichment of the transcription factor MAZ was detected in the promoter region of PSMD14, which enhanced PSMD14 transcription. Ethyl ferulate treatment downregulated MAZ expression, thereby reducing PSMD14 transcription.</div></div><div><h3>Conclusion</h3><div>Inhibition of the deubiquitinase PSMD14 to activate the Keap1/Nrf2 pathway may represent a mechanism by which ethyl ferulate suppresses CNV, supporting its promising prospects as a potential therapeutic candidate for CNV.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"153 ","pages":"Article 157913"},"PeriodicalIF":8.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146116349","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}
Pub Date : 2026-04-01Epub Date: 2026-01-30DOI: 10.1016/j.phymed.2026.157899
Ying Yang , Luchanghao Zheng , Tao Zhao , Yi Zhang , Ruiguang Luo , Shiyan Xie , Guilan Wen , Zhujun Cheng , Tianyu Han
Background
Pyroptosis is a form of inflammatory programmed cell death and has been proven to be a promising therapeutic strategy for cancer. To date, little is known about the natural product inducers of pyroptosis. Baohuoside I is a flavonoid compound extracted from plants of the Epimedium genus and has been reported to have antitumor effects. However, the mechanisms underlying Baohuoside I-induced cell death in lung adenocarcinoma (LUAD) remain unclear.
Purpose
To explore the effects and mechanisms of Baohuoside I-induced cell death in LUAD.
Methods
A cell counting kit-8 (CCK-8) was used to examine the inhibitory effects of Baohuoside I on LUAD cells. Cell death was detected by LDH release and PI staining. Cell membrane separation followed by western blotting and fluorescence microscopy were used to detect the cleavage and membrane translocation of GSDME. RNA sequencing was used to evaluate changes in overall gene expression.
Results
Baohuoside I induced significant cell death in LUAD cells, and this effect could be blocked by pyroptosis inhibitors rather than other cell death inhibitors or ROS scavengers. Further studies demonstrated that Baohuoside I treatment induced the cleavage and membrane translocation of GSDME, leading to pyroptosis. Through RNA sequencing analysis, we found that Baohuoside I inhibited the DNA damage repair process and that combined treatment with and cisplatin had a synergistic effect on LUAD.
Conclusion
Baohuoside I is a new pyroptosis inducer in LUAD, and combined treatment with Baohuoside I and cisplatin has a synergistic inhibitory effect on LUAD.
{"title":"Baohuoside I induces GSDME-dependent pyroptosis and synergistically inhibits lung adenocarcinoma with cisplatin","authors":"Ying Yang , Luchanghao Zheng , Tao Zhao , Yi Zhang , Ruiguang Luo , Shiyan Xie , Guilan Wen , Zhujun Cheng , Tianyu Han","doi":"10.1016/j.phymed.2026.157899","DOIUrl":"10.1016/j.phymed.2026.157899","url":null,"abstract":"<div><h3>Background</h3><div>Pyroptosis is a form of inflammatory programmed cell death and has been proven to be a promising therapeutic strategy for cancer. To date, little is known about the natural product inducers of pyroptosis. Baohuoside I is a flavonoid compound extracted from plants of the <em>Epimedium genus</em> and has been reported to have antitumor effects. However, the mechanisms underlying Baohuoside I-induced cell death in lung adenocarcinoma (LUAD) remain unclear.</div></div><div><h3>Purpose</h3><div>To explore the effects and mechanisms of Baohuoside I-induced cell death in LUAD.</div></div><div><h3>Methods</h3><div>A cell counting kit-8 (CCK-8) was used to examine the inhibitory effects of Baohuoside I on LUAD cells. Cell death was detected by LDH release and PI staining. Cell membrane separation followed by western blotting and fluorescence microscopy were used to detect the cleavage and membrane translocation of GSDME. RNA sequencing was used to evaluate changes in overall gene expression.</div></div><div><h3>Results</h3><div>Baohuoside I induced significant cell death in LUAD cells, and this effect could be blocked by pyroptosis inhibitors rather than other cell death inhibitors or ROS scavengers. Further studies demonstrated that Baohuoside I treatment induced the cleavage and membrane translocation of GSDME, leading to pyroptosis. Through RNA sequencing analysis, we found that Baohuoside I inhibited the DNA damage repair process and that combined treatment with and cisplatin had a synergistic effect on LUAD.</div></div><div><h3>Conclusion</h3><div>Baohuoside I is a new pyroptosis inducer in LUAD, and combined treatment with Baohuoside I and cisplatin has a synergistic inhibitory effect on LUAD.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"153 ","pages":"Article 157899"},"PeriodicalIF":8.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146116352","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}
Pub Date : 2026-04-01Epub Date: 2026-01-20DOI: 10.1016/j.phymed.2026.157860
Lingyuan Zeng , Shuwei Li , Kaidong Wu , Xiaoyu Bai , Long Zhang
Osteosarcoma (OS) is an aggressive primary bone malignancy characterized by limited therapeutic options and poor prognosis in advanced stages. Guggulsterone (GS), a naturally occurring plant-derived sterol, has recently been reported to suppress OS progression by inhibiting glycolysis via the MAPK signaling pathway. Although these findings underscore the therapeutic potential of GS in OS, the contribution of mitochondrial quality control to its antitumor activity remains unclear. Here, we report that GS disrupts mitochondrial integrity, elevates oxidative stress, and drives enhanced mitophagy in OS cells. RNA sequencing combined with functional assays revealed significant enrichment of mitophagy-related pathways, while rescue experiments confirmed that blocking mitophagy or SIRT3 activity markedly alleviated GS-induced mitochondrial damage, apoptosis, and growth inhibition. Mechanistically, GS activated the SIRT3-dependent PINK1/Parkin axis in a time-dependent manner, providing compelling evidence for its involvement in mitophagy regulation. Importantly, GS markedly inhibited OS tumor growth in vivo without causing detectable systemic toxicity. Collectively, our findings identify a mechanism distinct from the previously reported glycolysis/MAPK pathway, thereby broadening the mechanistic understanding of GS and underscoring its potential as a mitochondria-targeted therapeutic strategy for OS.
{"title":"Anti-tumor effects of Guggulsterone in osteosarcoma: Role of SIRT3-mediated PINK1-Parkin mitophagy activation","authors":"Lingyuan Zeng , Shuwei Li , Kaidong Wu , Xiaoyu Bai , Long Zhang","doi":"10.1016/j.phymed.2026.157860","DOIUrl":"10.1016/j.phymed.2026.157860","url":null,"abstract":"<div><div>Osteosarcoma (OS) is an aggressive primary bone malignancy characterized by limited therapeutic options and poor prognosis in advanced stages. Guggulsterone (GS), a naturally occurring plant-derived sterol, has recently been reported to suppress OS progression by inhibiting glycolysis via the MAPK signaling pathway. Although these findings underscore the therapeutic potential of GS in OS, the contribution of mitochondrial quality control to its antitumor activity remains unclear. Here, we report that GS disrupts mitochondrial integrity, elevates oxidative stress, and drives enhanced mitophagy in OS cells. RNA sequencing combined with functional assays revealed significant enrichment of mitophagy-related pathways, while rescue experiments confirmed that blocking mitophagy or SIRT3 activity markedly alleviated GS-induced mitochondrial damage, apoptosis, and growth inhibition. Mechanistically, GS activated the SIRT3-dependent PINK1/Parkin axis in a time-dependent manner, providing compelling evidence for its involvement in mitophagy regulation. Importantly, GS markedly inhibited OS tumor growth <em>in vivo</em> without causing detectable systemic toxicity. Collectively, our findings identify a mechanism distinct from the previously reported glycolysis/MAPK pathway, thereby broadening the mechanistic understanding of GS and underscoring its potential as a mitochondria-targeted therapeutic strategy for OS.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"153 ","pages":"Article 157860"},"PeriodicalIF":8.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146132961","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}
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