Pharmacological research最新文献

{"title":"Genetic and pharmacological targeting of HINT2 promotes OXPHOS to alleviate inflammatory responses and cell necrosis in acute pancreatitis","authors":"Jiaqi Yao ,&nbsp;Yuhong Jiang ,&nbsp;Pengcheng Zhang ,&nbsp;Yifan Miao ,&nbsp;Xiajia Wu ,&nbsp;Hang Lei ,&nbsp;Zhijun Xie ,&nbsp;Yong Tian ,&nbsp;Xianlin Zhao ,&nbsp;Juan Li ,&nbsp;Lv Zhu ,&nbsp;Meihua Wan ,&nbsp;Wenfu Tang","doi":"10.1016/j.phrs.2025.107620","DOIUrl":"10.1016/j.phrs.2025.107620","url":null,"abstract":"<div><div>The necrosis of pancreatic acinar cells is a key molecular event in the progression of acute pancreatitis (AP), with disturbances in mitochondrial energy metabolism considered to be a direct causative factor of acinar cell necrosis. Histidine triad nucleotide-binding protein 2 (HINT2) has been implicated in the development of various diseases, whereas its involvement in the progression of AP remains unclear. This study aims to investigate the role of HINT2 in AP. HINT2 expression in pancreatic tissues was significantly downregulated after AP. The results of glutathione-S-transferase (GST) pull-down and proteomics analyses revealed the involvement of HINT2 in regulating mitochondrial oxidative phosphorylation (OXPHOS) in AP mice. Moreover, lentivirus-mediated HINT2 overexpression not only alleviated AP-induced ATP depletion, but also relieved inflammatory responses and cell necrosis. Mechanistically, HINT2 interacted with cytochrome C oxidase II (MTCO2) to promote mitochondrial OXPHOS, thereby reducing ROS accumulation and inhibiting the activation of inflammatory signaling pathway. Besides, HINT2 act as a direct pharmacological target of Emo to elicit protective effects on AP. Importantly, Emo upregulates the expression of HINT2 and OXPHOS complex proteins and enhances the interaction between HINT2 and MTCO2. Furthermore, CRISPR/Cas9-mediated HINT2 knockout significantly impaired the protective effects of Emo against AP-induced mitochondrial energy metabolism disorders, inflammatory responses, and acinar cell necrosis<em>.</em> Overall, these results uncover a previously unexplored role for HINT2 in maintaining mitochondrial energy metabolism in pancreatic acinar cells and reveals novel mechanism and target for Emo-mediated AP remission.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107620"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein kinase inhibitors as targeted therapy for glioblastoma: a meta-analysis of randomized controlled clinical trials","authors":"José Pinto-Fraga ,&nbsp;Celia García-Chico ,&nbsp;Simone Lista ,&nbsp;Pedro Miguel Lacal ,&nbsp;Giuseppe Carpenzano ,&nbsp;Maurizio Salvati ,&nbsp;Alejandro Santos-Lozano ,&nbsp;Grazia Graziani ,&nbsp;Claudia Ceci","doi":"10.1016/j.phrs.2024.107528","DOIUrl":"10.1016/j.phrs.2024.107528","url":null,"abstract":"<div><div>Glioblastoma (GBM) is the most common and lethal primary brain tumor. The standard treatment for newly diagnosed GBM includes surgical resection, when feasible, followed by radiotherapy and temozolomide-based chemotherapy. Upon disease progression, the anti-vascular endothelial growth factor-A (VEGF-A) monoclonal antibody bevacizumab, can be considered.</div><div>Given the limited efficacy of pharmacological treatments, particularly for the recurrent disease, several molecularly targeted interventions have been explored, such as small-molecule protein kinase inhibitors (PKIs), inhibiting tyrosine kinase growth factor receptors and downstream signaling pathways involved in GBM angiogenesis and infiltrative behavior.</div><div>This meta-analysis, based on searches in PubMed and Web Of Science, evaluated 12 randomized controlled trials (RCTs) examining PKIs in patients with newly diagnosed or recurrent GBM. Pooled analysis of shared clinical outcomes - progression-free survival (PFS) and overall survival (OS) - revealed a lack of significant improvements with the use of PKIs. In newly diagnosed GBM, no significant differences were observed in median [-1.02 months, 95 % confidence interval (CI), −2.37–0.32, <em>p = 0.14</em>] and pooled [hazard ratio (HR) = 1.13, 95 % CI, 0.95–1.35, <em>p = 0.17</em>) OS, or in median (0.34 months, 95 % CI, −0.9–1.58, <em>p = 0.60</em>) and pooled (HR = 0.98, 95 % CI, 0.76–1.27, <em>p = 0.89</em>) PFS, when comparing PKI addition to standard chemo-radiotherapy <em>versus</em> chemo-radiotherapy alone. In recurrent GBM, three different analyses were conducted: PKI <em>versus</em> other treatments, PKI combined with other treatments <em>versus</em> those treatments alone, PKI <em>versus</em> PKI combined with other treatments. Also, across these analyses, no significant clinical benefits were found. For instance, when comparing PKI treatment with other treatments, median OS and PFS showed no significant difference (-0.78 months, 95 % CI, −2.12–0.55, <em>p = 0.25;</em> −0.23 months, 95 % CI, −0.79–0.34, <em>p = 0.43,</em> respectively), and similar non-significant results were observed in the pooled analyses (OS: HR = 0.89, 95 % CI, 0.59–1.32, <em>p = 0.55</em>; PFS: HR = 0.83, 95 % CI, 0.63–1.11, <em>p = 0.21</em>).</div><div>Despite these overall negative findings, some data indicate improved clinical outcomes in a subset of GBM patients treated with certain PKIs (i.e., regorafenib) and encourage further research to identify PKIs with better blood-brain barrier penetration and lower risk for resistance development.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107528"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142786403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling the pathogenesis of bone marrow hematopoietic injury and the therapeutic potential of natural products","authors":"Jing Long ,&nbsp;Hengzhou Lai ,&nbsp;Yuqing Huang ,&nbsp;Fengming You ,&nbsp;Yifang Jiang ,&nbsp;Qixuan Kuang","doi":"10.1016/j.phrs.2025.107589","DOIUrl":"10.1016/j.phrs.2025.107589","url":null,"abstract":"<div><div>Bone marrow hematopoietic injury encompasses a range of pathological conditions that disrupt the normal function of the hematopoietic system, primarily through the impaired production and differentiation of bone marrow hematopoietic cells. Key pathogenic mechanisms include aging, radiation damage, chemical induction, infection and inflammation, and cross-talk with non-hematopoietic diseases. These pathological factors often lead to myelosuppression and myeloid skewing. Furthermore, we explored the potential and application prospects of natural products in the treatment of bone marrow hematopoietic injury. Natural products, particularly those derived from Chinese herbal medicines and other natural sources, have emerged as promising therapeutic options due to their distinctive mechanisms and minimal side effects. A deeper understanding of the underlying mechanisms of bone marrow hematopoietic injury could illuminate how natural products exert their effects, thereby optimizing treatment strategies and offering safer, more effective options for patients. Future research should leverage emerging technologies to further elucidate the composition and interactions within the bone marrow microenvironment, as well as the specific pathways through which natural products modulate hematopoietic dysfunction.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107589"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142952904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Muribaculum intestinale-derived 3-hydroxybutyric acid from Heterophyllin B attenuated pulmonary fibrosis through IDO1-mediated ferroptosis","authors":"Ce Chen ,&nbsp;Jialin Wang ,&nbsp;Mengqin Cheng ,&nbsp;Haifeng Xie ,&nbsp;Wei Li ,&nbsp;Chaofeng Zhang","doi":"10.1016/j.phrs.2025.107587","DOIUrl":"10.1016/j.phrs.2025.107587","url":null,"abstract":"<div><div>Pulmonary fibrosis (PF) is a fatal disease with increasing incidence, poor prognosis, and unclear pathogenesis. Our previous research demonstrated the beneficial effects of the natural cyclopeptide Heterophyllin B (HB) in PF. However, the precise mechanism by which HB exerts its effects in PF remains unclear. Our study revealed HB's beneficial effects in alleviating PF symptoms and restoring the intestinal mucosal barrier. Subsequently, the microbiota-dependent antifibrotic efficacy of HB was verified using various delivery routes, antibiotic treatments, and faecal microbiota transplantation. Functionally, 16S rRNA sequencing, untargeted metabolomics, and co-incubation experiments revealed that the antifibrotic efficacy of HB was primarily contingent on the enrichment of <em>Muribaculum intestinale</em> and its metabolite, 3-hydroxybutyric acid. Mechanistically, indoleamine 2,3- dioxygenase 1 (IDO1)-mediated ferroptosis was identified as a pivotal process in initiating PF, and the anti-fibrotic efficacy of HB relies on suppressing IDO1-mediated ferroptosis. Conversely, IDO1 deficiency alleviated the symptoms of bleomycin-induced PF and ferroptosis in mice. Coincidentally, both IDO1 overexpression and ferroptosis were observed in the pulmonary tissue of patients with idiopathic PF. Collectively, this study revealed that HB alleviates PF by eliminating intestinal microecology and metabolism and highlights the feasibility of targeting IDO1 for PF treatment.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107587"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142952957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Noncoding RNAs in sepsis-associated acute liver injury: Roles, mechanisms, and therapeutic applications","authors":"Jialian Wang ,&nbsp;Xingyu Tao ,&nbsp;Zhengyang Liu ,&nbsp;Yuan Yan ,&nbsp;Peifeng Cheng ,&nbsp;Bin Liu ,&nbsp;Huimin Du ,&nbsp;Bailin Niu","doi":"10.1016/j.phrs.2025.107596","DOIUrl":"10.1016/j.phrs.2025.107596","url":null,"abstract":"<div><div>Sepsis is a life-threatening syndrome characterized by organ dysfunction caused by a dysregulated host response to infection. Sepsis-associated acute liver injury (SA-ALI) is a frequent and serious complication of sepsis that considerably impacts both short-term and long-term survival outcomes. In intensive care units (ICUs), the mortality rate of patients with SA-ALI remains high, mostly due to the absence of effective early diagnostic markers and suitable therapeutic strategies. Recent studies have demonstrated the importance of non-coding RNAs (ncRNAs) in the development and progression of SA-ALI. This review focuses on the critical roles of ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), in regulating “cytokine storms”, oxidative stress, mitochondrial dysfunction, and programmed cell death in SA-ALI, and summarizes the current state and limitations of existing studies on lncRNAs and circRNAs in SA-ALI. By integrating advancements in high-throughput sequencing technologies, this review provides novel insights into the dual potential of ncRNAs as diagnostic biomarkers and therapeutic targets, offers new ideas for SA-ALI diagnosis and treatment research and highlights potential challenges in clinical translation.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107596"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting MYCN upregulates L1CAM tumor antigen in MYCN-dysregulated neuroblastoma to increase CAR T cell efficacy","authors":"Laura Grunewald ,&nbsp;Lena Andersch ,&nbsp;Konstantin Helmsauer ,&nbsp;Silke Schwiebert ,&nbsp;Anika Klaus ,&nbsp;Anton G. Henssen ,&nbsp;Teresa Straka ,&nbsp;Marco Lodrini ,&nbsp;Sebastian G. Wicha ,&nbsp;Steffen Fuchs ,&nbsp;Falk Hertwig ,&nbsp;Frank Westermann ,&nbsp;Alice Vitali ,&nbsp;Carlotta Caramel ,&nbsp;Gabriele Büchel ,&nbsp;Martin Eilers ,&nbsp;Kathy Astrahantseff ,&nbsp;Angelika Eggert ,&nbsp;Uta E. Höpken ,&nbsp;Johannes H. Schulte ,&nbsp;Annette Künkele","doi":"10.1016/j.phrs.2025.107608","DOIUrl":"10.1016/j.phrs.2025.107608","url":null,"abstract":"<div><div>Current treatment protocols have limited success against <em>MYCN-</em>amplified neuroblastoma. Adoptive T cell therapy presents an innovative strategy to improve cure rates. However, L1CAM-targeting CAR T cells achieved only limited response against refractory/relapsed neuroblastoma so far. We investigated how oncogenic MYCN levels influence tumor cell response to CAR T cells, as one possible factor limiting clinical success. A MYCN-inducible neuroblastoma cell model was created. L1CAM-CAR T cell effector function was assessed (activation markers, cytokine release, tumor cytotoxicity) after coculture with the model or <em>MYCN</em>-amplified neuroblastoma cell lines. RNA sequencing datasets characterizing the model were compared to publicly available RNA/proteomic datasets. MYCN-directed <em>L1CAM</em> regulation was explored using public ChIP-sequencing datasets. Synergism between CAR T cells and the indirect MYCN inhibitor, MLN8237, was assessed <em>in vitro</em> using the Bliss model and <em>in vivo</em> in an immunocompromised mouse model. Inducing high MYCN levels in the neuroblastoma cell model reduced L1CAM expression and, consequently, L1CAM-CAR T cell effector function <em>in vitro</em>. Primary neuroblastomas possessing high <em>MYCN</em> levels expressed lower levels of both the <em>L1CAM</em> transcript and L1CAM tumor antigen. MLN8237 treatment restored L1CAM tumor expression and L1CAM-CAR T cell effector function. Combining MLN8237 and L1CAM-CAR T cell treatment synergistically enhanced MYCN-overexpressing tumor cytotoxicity <em>in vitro</em> and <em>in vivo</em> concomitant with severe <em>in vivo</em> toxicity. We identify target antigen downregulation as source of resistance against L1CAM-CAR T cells in MYCN-driven neuroblastoma cells. These data suggest that L1CAM-CAR T cell therapy combined with pharmacological MYCN inhibition may benefit patients with <em>MYCN</em>-amplified neuroblastoma.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107608"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143009541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AlphaFold-based AI docking reveals AMPK/SIRT1-TFEB pathway modulation by traditional Chinese medicine in metabolic-associated fatty liver disease","authors":"Lulu Zhang ,&nbsp;Yi Zheng ,&nbsp;Mingyan Shao ,&nbsp;Aiping Chen ,&nbsp;Meiyi Liu ,&nbsp;Wenlong Sun ,&nbsp;Tianxing Li ,&nbsp;Yini Fang ,&nbsp;Yang Dong ,&nbsp;Shipeng Zhao ,&nbsp;Hui Luo ,&nbsp;Juan Feng ,&nbsp;Qi Wang ,&nbsp;Lingru Li ,&nbsp;Yanfei Zheng","doi":"10.1016/j.phrs.2025.107617","DOIUrl":"10.1016/j.phrs.2025.107617","url":null,"abstract":"<div><div>Metabolic-associated fatty liver disease (MAFLD) is a chronic, progressive disorder characterized by hepatic steatosis and excessive lipid accumulation. Its high global adult prevalence (approximately 50.7 %) is a significant concern worldwide. However, FDA-approved therapeutic drugs remains lacking. Qigui Jiangzhi Formula (QGJZF) shows promise in treating MAFLD by effectively decreasing lipid levels and improving hepatic steatosis, however its mechanisms remain unclear. This study investigated QGJZF’s effects in high-fat diet-induced zebrafish and golden hamsters, and in palmitate (PA) and oleic acid (OA) - induced HepG2 cells, using the SymMap database to identify potential targets and pathways of QGJZF in MAFLD and AlphaFold algorithms to predict protein structures. <em>In vivo,</em> QGJZF significantly alleviated hepatic lipid deposition. Intriguingly, QGJZF decreased lipid droplets and its levels are negative correlated with the numbers of autolysosomes, indicating that QGJZF’s mechanism of ameliorating liver lipid deposition may be related to the regulation of autophagy. QGJZF upregulated the expressions of phosphorylated -Adenosine 5‘-monophosphate (AMP) - activated protein kinase (p-AMPK), Sirtuin deacetylase 1 (SIRT1) and Transcription factor EB (TFEB), accompanied by the changes in autophagy-related proteins. <em>In vitro</em>, QGJZF inhibited the lipid deposition in PA/OA-stimulated HepG2 cells, and its effect was blocked by an autophagy inhibitor Baf-A1, which was mediated through upregulation of TFEB and its mediated autophagy-lysosomal pathway. Moreover, cotreatment with AMPK inhibitor Compound C, the regulation of QGJZF on TFEB, SIRT1, autophagy-related protein levels, and lipid deposition were reversed. Network pharmacology identified the PRKAA2 (AMPK) and SIRT1 as key hub targets. Futher analysis of their structures using AlphaFold3 algorithms, yielded high-ranking scores of 0.97 and 0.93, respectively. Liquid chromatography-mass spectrometry combined with molecular docking expounded its five compounds in QGJZF binding to AMPK protein. These findings suggest that QGJZF as a therapeutic agent in augmenting autophagy-facilitated lipid clearance for the management of MAFLD via AMPK/SIRT1-TFEB axis.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107617"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143009735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ginseng polysaccharides circumvent acquired resistance to anti-PD-1 immunotherapy in patients with non-small cell lung cancer","authors":"Jumin Huang ,&nbsp;Ziming Wang ,&nbsp;Feng Li ,&nbsp;Huiting Wang,&nbsp;Yang Xiang,&nbsp;Runze Li,&nbsp;Chun Xie,&nbsp;Yuwei Wang,&nbsp;Zhihong Jiang,&nbsp;Yabing Cao,&nbsp;Wenhua Liang,&nbsp;Elaine Lai-Han Leung","doi":"10.1016/j.phrs.2025.107611","DOIUrl":"10.1016/j.phrs.2025.107611","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107611"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143009341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sailing south from regulations to strategies: Macau as a promising gateway for the export of proprietary Chinese medicines to ASEAN countries","authors":"Dong-mei Xue,&nbsp;Dan-ni Wang,&nbsp;Jia Yuan,&nbsp;Lan Yao,&nbsp;Ying Bian","doi":"10.1016/j.phrs.2025.107600","DOIUrl":"10.1016/j.phrs.2025.107600","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107600"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143009472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the benefits and prescribing informations of combining East Asian herbal medicine with conventional medicine in the treatment of rheumatoid arthritis: A systematic review and multifaceted analysis of 415 randomized controlled trials","authors":"Hee-Geun Jo ,&nbsp;Jihye Seo ,&nbsp;Eunhye Baek ,&nbsp;Donghun Lee","doi":"10.1016/j.phrs.2025.107616","DOIUrl":"10.1016/j.phrs.2025.107616","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Notwithstanding progress in conventional medicine (CM), the management of rheumatoid arthritis (RA) continues to be problematic due to factors such as limited patient response to treatment and restricted medication access. This study aimed to evaluate the extent to which East Asian herbal medicine with CM combination therapy (EACM) provides additional benefits in effectiveness and safety.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;We conducted a comprehensive search across 11 databases in English, Chinese, Korean, and Japanese for randomized controlled trials. The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, using the American College of Rheumatology (ACR) 20/50/70 Response Criteria and the incidence of adverse events (AEI) as primary outcomes. This meta-analysis was performed using a random-effects model. The quality of each study was assessed according to the RoB 2. Of the 1036 full-text articles screened, 415 were included in the review.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;This review included data from 37,839 participants. EACM was associated with higher ACR responses: ACR 20 (RR: 1.2332; 95 % CI: 1.1852–1.2831, p &lt; 0.0001), ACR 50 (RR: 1.3782; 95 % CI: 1.2936–1.4684, p &lt; 0.0001), and ACR 70 (RR: 1.7084; 95 % CI: 1.5555–1.8762, p &lt; 0.0001), as well as a favorable AEI (OR: 0.3977; 95 % CI: 0.3476–0.4551, p &lt; 0.0001), indicating both better efficacy and safety compared to CM alone. These patterns were consistent across eight secondary outcomes measuring pain, inflammation, and disease activity in RA. Subgroup analyses showed that EACM's effects were independent of the control CM type. Through a comprehensive analysis of a polyherbal prescription dataset, we identified 18 key herbs and 16 significant combination rules, further supported by relevant preclinical evidence. These herbs and synergistic herbal combinations were anticipated to be the most pharmacologically influential in contributing to the meta-analysis outcomes, as substantiated by analytical metrics including network topology and intricate association pattern evaluations.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;The findings suggest that EACM may serve as a valuable complementary strategy for RA patients insufficiently managed by CM alone. In particular, given that the ACR index integrates multiple aspects of RA patients, the results are expected to provide valuable complementary decision support for the management of RA patients who do not respond well to CM therapy, both for medical and economic reasons. Additionally, the key herbs derived through the multifaceted analysis, which actively reflect clinicians' implicit preferences for prescribing EACMs, may serve as important hypotheses for further research and clinical application. However, additional qualitative and quantitative improvements in research are needed for more definitive conclusions. Further analysis of the herbal prescriptions p","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"212 ","pages":"Article 107616"},"PeriodicalIF":9.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143040819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}