The American journal of Chinese medicine最新文献

{"title":"Brain-Gut Axis Perspective on Irritable Bowel Syndrome: The Role of Gut Microbiota and Therapeutic Strategies of Traditional Chinese Medicine.","authors":"Anping Yu, Yanru Bi, Xiao Xu","doi":"10.1142/S0192415X26500771","DOIUrl":"https://doi.org/10.1142/S0192415X26500771","url":null,"abstract":"<p><p>Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders, with dysfunction of the gut-brain axis (GBA) being its core pathogenic mechanism. Traditional Chinese Medicine (TCM), guided by the theory of \"liver-spleen interaction\" and the core therapeutic principle of \"soothing the liver and invigorating the spleen\", has accumulated extensive clinical experience in IBS treatment. This review systematically searched PubMed, Web of Science, and CNKI databases to summarize the molecular mechanisms by which gut microbiota participate in IBS pathogenesis through the GBA, interpret the modern biological connotation of the TCM pathogenesis of \"liver depression and spleen deficiency\" from the perspective of the GBA, and review the evidence for TCM in treating IBS by modulating gut microbiota. The results indicate that gut microbiota dysbiosis drives IBS symptoms through three major metabolic pathways - short-chain fatty acids, bile acids, and 5-hydroxytryptamine - and achieves bidirectional regulation via the GBA. TCM monomers (e.g., berberine, curcumin, apigenin), single herbs (e.g., <i>Atractylodes</i>, <i>Cinnamomum</i>, Liupao tea), classical formulas (e.g., Tong-Xie-Yao-Fang, Chang-Kang-Fang, Si-Ni-San), as well as acupuncture and moxibustion, may improve IBS symptoms by restoring gut microbial diversity, regulating metabolite levels, repairing the intestinal barrier, and inhibiting inflammatory pathways. TCM may offer unique advantages in treating IBS through multi-target regulation of gut microbiota. Future research should focus on the objectification of TCM syndrome differentiation based on gut microbiota and the development of precision matching strategies.</p>","PeriodicalId":94221,"journal":{"name":"The American journal of Chinese medicine","volume":" ","pages":"1-30"},"PeriodicalIF":5.5,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149121124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Silybin for Liver Diseases via Anti-Oxidative Stress: A Comprehensive Review.","authors":"Chao Cui, Jingfei Shi, Yu Sun, Shuai Gao, Kai Wang","doi":"10.1142/S0192415X25500910","DOIUrl":"10.1142/S0192415X25500910","url":null,"abstract":"<p><p>Liver diseases pose a significant challenge in global public health, and scientific prevention and treatment strategies have become particularly crucial. Silybin, a flavonoid and active ingredient extracted from the traditional Chinese medicinal herb milk thistle, is the most critical effective component in silymarin, and has clearly demonstrated potent anti-oxidative stress capabilities. This unique attribute makes it a highly promising drug candidate for treating acute hepatitis, chronic hepatitis, cirrhosis, liver cancer, and other liver diseases. In the progression of liver diseases, silybin exerts significant therapeutic effects via dual anti-oxidant and anti-inflammatory mechanisms through which it alleviates the inflammatory response in acute hepatitis, stabilizes the progression of chronic hepatitis, and promotes the benign transition from decompensated to compensated cirrhosis. This study comprehensively reviews research findings on silybin in treating liver diseases via this anti-oxidative stress mechanism over the past few decades, and offers a particular focus on the development of novel drug formulations based on the oxidative stress pathogenesis of liver diseases. These formulations target the CD44 receptor, retinol/vitamin A, CXCR4 receptor, glycyrrhetinic acid receptor, GLUT4 protein, NS5B protein, and SPARC. It also examines the current status of the anti-oxidant and anti-inflammatory applications of silybin formulations in global liver disease treatments. However, more high-quality, detailed experimental studies are needed to explore its exact efficacy and safety so as to provide a stronger scientific basis for the widespread application of silybin in liver disease treatment.</p>","PeriodicalId":94221,"journal":{"name":"The American journal of Chinese medicine","volume":" ","pages":"1-34"},"PeriodicalIF":5.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145914373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Angelica sinensis</i>: Botany, Traditional Uses, Phytochemistry, Pharmacology, Safety, and Applications.","authors":"Yanjuan Zhang, Zemei Zhu, Xinru Li, Qingjun Shu, Yaping Wang, Baozhong Duan","doi":"10.1142/S0192415X2650045X","DOIUrl":"https://doi.org/10.1142/S0192415X2650045X","url":null,"abstract":"<p><p><i>Angelica sinensis</i> (Oliv.) Diels (<i>A. sinensis</i>), a perennial herb with a medicinal history spanning over two millennia, is widely recognized for its effects in nourishing blood, promoting circulation, regulating menstruation, and alleviating pain. As demonstrated by over 1572 articles published since 2016, research in this field has advanced rapidly. However, the most recent comprehensive review dates back to 2016, and lacks systematic coverage of pharmacological mechanisms, structure-activity relationships (SARs), and modern applications. As a result, much of the relevant knowledge has been fragmented across disciplines. This review addresses these gaps by providing a systematic synthesis of the botany, traditional uses, phytochemistry, pharmacology, safety, and applications of <i>A. sinensis</i>. Over 290 chemical constituents, which can be broadly categorized into volatile oils, organic acids, polysaccharides, phenylpropanoids, and flavonoids, have been identified from <i>A. sinensis</i>to date. Representative bioactive compounds, such as <i>Z</i>-ligustilide (<i>Z</i>-lig), ferulic acid, and <i>angelica coumarin A</i>, contribute significantly to its diverse biological activities. This review offers an in-depth, mechanism-based summary of its pharmacological properties, and places a particular emphasis on the SARs of key bioactive constituents. The scope of the review is further expanded to include emerging applications in functional foods, skincare, agriculture, and animal husbandry industries. This review integrates multidisciplinary advances to establish a comprehensive and mechanistically grounded framework. This framework aims in turn to guide evidence-based utilization, foster innovative applications, and support the sustainable global development of <i>A. sinensis</i> as a medicinal and functional resource. However, several challenges remain in current research. These include insufficient standardization of cultivation practices, limited high-quality clinical evidence, and the lack of internationally recognized quality standards. Future research should prioritize multicenter clinical trials, the elucidation of biosynthetic pathways, and the establishment of international quality standards in order to promote the sustainable global development of <i>A. sinensis</i>.</p>","PeriodicalId":94221,"journal":{"name":"The American journal of Chinese medicine","volume":"54 4","pages":"1213-1251"},"PeriodicalIF":5.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148348073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut Microbiota as Neuroimmune Modulators in Myasthenia Gravis: Mechanistic Insights from the Gut-Brain Axis to Therapeutic Innovations.","authors":"Jie Lv, Ruichen Liu, Zhan Sun, Jing Zhang, Yingna Zhang, Xue Zhao, Jing Liu, Xinyue Zhou, Mengdi Zhang, Qian Liu, Feng Gao","doi":"10.1142/S0192415X26500023","DOIUrl":"10.1142/S0192415X26500023","url":null,"abstract":"<p><p>Myasthenia gravis (MG) is a chronic autoimmune disorder characterized by an immune-mediated attack on neuromuscular junction acetylcholine receptors (AChRs), and its pathogenesis is closely linked to immune dysregulation. Emerging evidence has highlighted the pivotal role of the gut microbiota in the pathophysiology of MG through immunomodulation, microbial metabolite signaling, and gut-brain axis interactions. This review combines 16S rRNA sequencing, metagenomic, and metabolomic data to reveal distinct gut microbial signatures in patients with MG. These signatures include reduced α-diversity, depletion of beneficial taxa like <i>Bacteroides</i> and <i>Bifidobacterium</i>, enrichment of pathobionts such as <i>Escherichia</i> and <i>Enterococcus</i>, and diminished levels of the short-chain fatty acids (SCFA), which were inversely correlated with disease severity. Experimental models have demonstrated that fecal microbiota transplantation (FMT) and probiotic supplementation with strains like <i>Bifidobacterium</i> ameliorate symptoms by restoring Th17/Treg equilibrium, suppressing the expression of pro-inflammatory cytokines including IL-6 and TNF-α, and enhancing intestinal barrier integrity. Mechanistically, gut dysbiosis exacerbates autoimmunity via NF-αB pathway activation, disrupts tryptophan metabolism and impairs gut-brain signaling. While existing studies have established microbiota-MG associations, further causal validation, personalized therapeutic strategies, and multi-omics integration remain critical priorities. Microbiota-targeted interventions, including precision FMT and metabolite delivery, hold translational potential, but their validation via large-scale randomized controlled trials and interdisciplinary approaches like AI-driven microbiota profiling is essential if they are to advance precision medicine for MG management.</p>","PeriodicalId":94221,"journal":{"name":"The American journal of Chinese medicine","volume":" ","pages":"65-85"},"PeriodicalIF":5.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146069291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Mechanisms of Traditional Chinese Medicine in Treating Osteoarthritis.","authors":"Yaohong Lu, Haidong Zhou, Hui Luo, Wentao Hu, Liangshen Hu, Jiefei Xie, Xinping Wu, Bo Li, Junjie Zhou, Shaoyong Fan, Jichun Shan, Yuwen Chen, Fengting Zhang","doi":"10.1142/S0192415X2650028X","DOIUrl":"10.1142/S0192415X2650028X","url":null,"abstract":"<p><p>Osteoarthritis (OA) is a prevalent degenerative joint disease characterized by chronic inflammation, cartilage degradation, and disrupted cellular homeostasis. Traditional Chinese medicine (TCM) has been widely applied in OA management, and exhibits distinct therapeutic advantages due to its multi-component and multi-target pharmacological properties. This review summarizes the molecular mechanisms by which TCM exerts therapeutic effects in OA, and offers a particular focus on the modulation of key signaling pathways involved in inflammation, apoptosis, autophagy, oxidative stress, and cartilage metabolic balance. Relevant studies were retrieved from the PubMed, Web of Science, Embase, and ScienceDirect databases, from their inception up to November 2025, and systematically analyzed. Evidence from experimental studies involving representative active compounds (e.g., Icariin, Geniposide, Ginsenoside Rb1, and Bilobalide) and classical formulas (such as Duhuo Jisheng Decoction, Yougui Pills, and Osteoking) indicates that TCM alleviates inflammation by inhibiting NF-κB, MAPK, and JAK/STAT signaling; promotes autophagy and metabolic homeostasis through regulation of the PI3K/Akt and AMPK pathways; attenuates oxidative stress via activation of the Nrf2 pathway; and maintains cartilage matrix equilibrium by modulating Wnt/β-catenin, TGF-β/Smad, and Notch signaling. TCM therefore exerts disease-modifying effects in OA through coordinated regulation of multiple signaling pathways, which both highlights its ethnopharmacological value and supports the rational development of TCM-based therapeutic strategies for OA.</p>","PeriodicalId":94221,"journal":{"name":"The American journal of Chinese medicine","volume":" ","pages":"763-793"},"PeriodicalIF":5.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147730933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Effectiveness and Safety of Chinese Herbal Enema for Ulcerative Colitis: An Evidence-Based Study.","authors":"Zhijun Bu, Jinchen Chong, Jiaze Ma, Yimeng Ma, Feng Jiang, Yugen Chen","doi":"10.1142/S0192415X26500047","DOIUrl":"10.1142/S0192415X26500047","url":null,"abstract":"<p><p>Ulcerative colitis (UC) is a common, chronic, and nonspecific inflammatory bowel disease which significantly impair patients' quality of life, and is characterized by a prolonged disease course and frequent relapses. Due to their localized therapeutic action and low incidence of adverse effects, Chinese herbal enemas have garnered increasing attention in clinical settings. This study aims to systematically evaluate the therapeutic potential of Chinese herbal enemas in UC management. Randomized controlled trials (RCTs) evaluating Chinese herbal enemas for UC, published up to April 19, 2025, were systematically searched. A network meta-analysis was performed using Stata 17.0, and the combined effect sizes were reported as the mean difference or relative risk with corresponding 95% confidence intervals. A total of 41 RCTs involving 2883 UC patients were ultimately included, and data on the risk of bias assessment were reported. When compared with mesalazine (MES) monotherapy, combination therapies, such as MES combined with Qingbai Guanchang Ye or MES combined with Qingchi San, and monotherapies including Huangkui Lianchang Tang and Baitouweng Tang, demonstrated statistically significant improvements in clinical outcomes. Subgroup analyses were also conducted. The clinical effectiveness of these interventions was also influenced by Traditional Chinese Medicine (TCM) syndrome differentiation and disease severity, which underscores the importance of individualized, stratified treatment approaches. Our study data showed that Chinese herbal enema therapy appears to be both clinically effective and safe in the management of UC, and supported both stratified TCM therapy and the refinement of UC treatment guidelines. Future research is needed to prioritize high-quality, large-scale RCTs to validate these findings.</p>","PeriodicalId":94221,"journal":{"name":"The American journal of Chinese medicine","volume":" ","pages":"117-138"},"PeriodicalIF":5.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146047687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Management of Type 2 Diabetes Mellitus: Targeting Gut Microbiome Therapy.","authors":"Aqsa Bibi, Li Zhou, Min You, Huifang Niu, Muhammad Wasim Tasleem, Huan Wu, Hongxing Zhang","doi":"10.1142/S0192415X26500497","DOIUrl":"10.1142/S0192415X26500497","url":null,"abstract":"<p><p>Marked by high blood glucose and systemic metabolic dysfunction, type 2 diabetes mellitus (T2DM) is a significant health issue with a rapidly increasing worldwide prevalence. Recent studies have highlighted the gut microbiota as a key determinant of host metabolism, and identified that the composition and metabolic activity are closely linked to the development and progression of T2DM. This review comprehensively explores the intricate connection between T2DM and the gut microbiota, with a particular focus on how traditional Chinese medicine (TCM) can influence intestinal microbiota composition to manage disease. It also discusses the therapeutic potential of TCM, which includes natural medicinal extracts like baicalin, berberine, tetrahydrocurcumin, ginsenoside Rb1, ophiopogonin D, and resveratrol, compound formulations, and acupuncture, in regulating the intestinal microbiota ecosystem to manage T2DM. Although the current evidence suggests that these interventions may slow T2DM progression, most studies have been confined to animal models and early clinical trials which lack adequate clinical evidence to confirm their efficacy. This discrepancy has created an imbalance between theoretical and validated clinical applications. Building on existing research, future research should focus on large-scale clinical trials and advanced multi-omics studies to uncover the potential of TCM in managing T2DM through the gut microbiota.</p>","PeriodicalId":94221,"journal":{"name":"The American journal of Chinese medicine","volume":" ","pages":"1331-1356"},"PeriodicalIF":5.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148407643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quercetin-Induced Ferroptosis Attenuates Pancreatic Ductal Adenocarcinoma via Facilitating NCOA4-Dependent Ferritinophagy.","authors":"Chang Li, Liya Zhou, Xunzhe Yin","doi":"10.1142/S0192415X2650059X","DOIUrl":"10.1142/S0192415X2650059X","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal of malignancies. Quercetin (QCT), a natural flavonoid, exhibits broad pharmacological activities and minimal toxicity, which makes it a promising candidate for cancer therapy. Ferroptosis, a form of cell death driven by iron-dependent lipid peroxidation, has emerged as a promising therapeutic target for cancer treatment. Emerging evidence highlights ferroptosis as a key tumor-suppressive mechanism because it directly kills tumor cells independently of apoptotic effectors and necrosis inducers. The focus of this work is to investigate the significance of QCT in inhibiting PDAC via ferroptosis induction. The antitumor effects of QCT on PDAC were investigated both <i>in vitro</i>, through analyses of cell proliferation and apoptosis, and <i>in vivo</i> by using tumor xenograft models. The <i>in vitro</i> validation results confirmed that QCT inhibited PDAC cell proliferation by modulating ferroptosis via the elevation of intracellular Fe[Formula: see text] and lipid peroxidation. In addition, QCT promoted autophagy by upregulating expression of LC3 and ATG5 autophagy-related proteins. Mechanistically, QCT sensitized PDAC cells to ferroptosis by facilitating NCOA4-mediated ferritinophagy to increase intracellular Fe[Formula: see text] content. Conversely, silencing NCOA4 further supported our mechanistic studies by restoring the downregulated mitochondrial respiration and glycolytic capacity. This study likewise served to demonstrate the significance of NCOA4-mediated ferritinophagy in promoting QCT-regulated tumor cell death. Taken together, our findings reveal the direct protein targets and molecular mechanisms through which QCT enhances antitumor activity, and thus suggest that the targeted induction of ferroptosis via QCT administration may represent a valuable and effective strategy for treating PDAC.</p>","PeriodicalId":94221,"journal":{"name":"The American journal of Chinese medicine","volume":" ","pages":"1607-1635"},"PeriodicalIF":5.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148427707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Notoginsenoside R1 Alleviates Acetaminophen-Induced Liver Injury via MAPK/mTOR-Mediated Autophagy.","authors":"Shuangjiang Li, Zhipeng Liu, Guandong Pan, Shuang Li, Guangyu Lv, Shifu Tang, Jiaguang Li, Qiuyun Li, Min Wu, Guandou Yuan, Shuiping Yu, Guoqing Ouyang","doi":"10.1142/S0192415X26500576","DOIUrl":"10.1142/S0192415X26500576","url":null,"abstract":"<p><p>Acetaminophen (APAP) overdose is a leading cause of acute liver injury (ALI), yet effective therapeutic options remain limited. Although notoginsenoside R1 (NGR1) is a major bioactive saponin isolated from <i>Panax notoginseng</i> with established anti-inflammatory and anti-oxidant properties, its hepatoprotective potential and underlying mechanisms in APAP-induced liver injury (AILI) have not been systematically investigated. In this study, we established an AILI mouse model and evaluated the protective effects of NGR1 through biochemical assays, histopathology, Western blotting, and immunofluorescence, complemented by integrative transcriptomic, metabolomic, and gut microbiota analyses. Mechanistic involvement of the MAPK/mTOR-autophagy pathway was further validated using L-leucine as a pharmacological activator of mTOR. NGR1 markedly attenuated AILI, as reflected by reduced serum ALT/AST levels, improved hepatic histology, and increased survival in acute liver failure. NGR1 suppressed inflammatory responses by decreasing IL-1[Formula: see text], IL-6, and TNF-[Formula: see text] levels and alleviated oxidative stress by restoring GSH and SOD while reducing MPO, ROS, and MDA accumulation. Multi-omics analysis revealed significant enrichment of MAPK/mTOR signaling, autophagy, ferroptosis, and glutathione metabolism pathways. Mechanistically, NGR1 promoted autophagic flux (increased LC3-II/I, ATG5, and ATG7 with decreased p62), inhibited ferroptosis (upregulation of GPX4 and SLC7A11 with downregulation of ACSL4), and suppressed APAP-induced activation of the MAPK/mTOR pathway. Pharmacological activation of mTOR by L-leucine partly abolished the protective effects of NGR1, reversing autophagy activation and restoring inflammatory and oxidative injury. These findings collectively demonstrate that NGR1 protects against AILI by inhibiting MAPK/mTOR signaling, restoring autophagy, and suppressing ferroptosis, highlighting NGR1 as a promising therapeutic candidate for APAP-induced hepatotoxicity.</p>","PeriodicalId":94221,"journal":{"name":"The American journal of Chinese medicine","volume":" ","pages":"1551-1583"},"PeriodicalIF":5.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148458179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ginseng-Containing Sijunzi Decoction Inhibits Colorectal Cancer Progression by Regulating MARCHF3-ALOX15-Mediated Ferroptosis.","authors":"Yong Gao, Guoqun Chen, Xinyu Jiang, Wenbin Gao, Zhengyong Li, He Zhao, Jiefeng Liu, Zhenquan Wang","doi":"10.1142/S0192415X26500709","DOIUrl":"10.1142/S0192415X26500709","url":null,"abstract":"<p><p>Colorectal cancer (CRC) frequently develops resistance to 5-fluorouracil (5-FU)-based chemotherapy, which remains a major obstacle to successful treatment. Ginseng-containing Sijunzi Decoction (SJZD), a classical Traditional Chinese Medicine formula, has demonstrated antitumor activity; however, whether and how SJZD enhances 5-FU sensitivity remains largely unclear. In this study, SJZD-containing serum was prepared and administered to 5-FU-resistant CRC cell lines (HCT116/5-FU and SW480/5-FU). Chemosensitivity was evaluated using Cell Counting Kit-8 (CCK-8) and Calcein-AM/propidium iodide (PI) staining assays, while ferroptosis was assessed by measuring oxidative stress-related indicators, including malondialdehyde (MDA), glutathione (GSH), reactive oxygen species (ROS), and intracellular ferrous iron (Fe[Formula: see text]) levels. In addition, a BALB/c nude mouse xenograft model was established to validate the synergistic antitumor effects of SJZD and 5-FU <i>in vivo</i>. Protein-protein interactions and ubiquitination were examined by co-immunoprecipitation and <i>in vitro</i> ubiquitination assays. Our results demonstrated that SJZD markedly enhanced the sensitivity of resistant CRC cells to 5-FU by inhibiting cell proliferation and promoting ferroptosis both <i>in vitro</i> and <i>in vivo</i>. In the xenograft model, combined treatment with SJZD and 5-FU produced significantly greater reductions in tumor volume and tumor weight than treatment with 5-FU alone. Furthermore, the ferroptosis inhibitor ferrostatin-1 (Fer-1) effectively abolished the chemosensitizing effect of SJZD, indicating that ferroptosis is required for SJZD-mediated reversal of 5-FU resistance. Mechanistically, SJZD suppressed the expression of the E3 ubiquitin ligase membrane-associated ring finger protein 3 (MARCHF3), thereby inhibiting the ubiquitination and proteasomal degradation of arachidonate 15-lipoxygenase (ALOX15), a critical regulator of ferroptosis. Rescue experiments further demonstrated that ALOX15 silencing or MARCHF3 overexpression significantly attenuated SJZD-induced ferroptosis and reversed its sensitizing effect on 5-FU-resistant CRC cells. Collectively, these findings demonstrate that SJZD enhances the chemosensitivity of CRC cells to 5-FU by activating ferroptosis through regulation of the MARCHF3/ALOX15 axis. This study provides mechanistic insight into the antitumor activity of SJZD and highlights its potential as a promising adjuvant strategy for overcoming 5-FU resistance in CRC.</p>","PeriodicalId":94221,"journal":{"name":"The American journal of Chinese medicine","volume":" ","pages":"1875-1897"},"PeriodicalIF":5.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148809693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}