Archives of Pharmacal Research最新文献

{"title":"Artemisinin attenuates 3-nitropropionic acid-induced neurodegeneration via HMGB1/TLR4/NF-κB modulation in a rat model of huntington’s disease","authors":"Aya M. Mustafa,&nbsp;Mustafa Mudhafar,&nbsp;Ali M. Elgindy,&nbsp;Manar M. Esmail,&nbsp;Ahmed M. Atwa,&nbsp;Aya M. Shaheen,&nbsp;Abdullah F. Radwan,&nbsp;Nourhan Elfar,&nbsp;Ruaa Yasir Altayeb Mohamed,&nbsp;Noha M. Gamil","doi":"10.1007/s12272-026-01604-1","DOIUrl":"10.1007/s12272-026-01604-1","url":null,"abstract":"<div><p>Huntington’s disease (HD) is a progressive neurodegenerative disorder characterized by motor, cognitive, and behavioral impairments associated with striatal neuronal loss, for which effective symptom-attenuating therapies remain lacking. Artemisinin (ART), a natural sesquiterpene lactone with established antioxidant and anti-inflammatory actions, has recently gained attention as a potential neuroprotective agent. This study evaluated the therapeutic relevance of ART in a rat model of HD induced by 3-nitropropionic acid (3-NP). 3-NP administration caused severe behavioral deficits, including an 81.8% reduction in rearing and a 74.9% reduction in ambulation (p &lt; 0.0001), a 63.7% decrease in novel object exploration, and a 53.5% decline in Morris water maze target quadrant time versus controls. Biochemically, 3-NP elevated HMGB1 (4.8-fold), TLR4 (6.8-fold), RIPK1 (6.4-fold), RIPK3 (5.2-fold), MLKL (5.5-fold), p38-MAPK (4.2-fold), NF-κB (2.1-fold), and TNF-α (4.5-fold), while reducing GSH (57.6%), Nrf2 (77.7%), Sig1R (86.2%), D2R (64%), XIAP (77.8%), BDNF (57.6%) and SDH (61.44%) (all p &lt; 0.0001). Treatment with ART (100 mg/kg) markedly restored behavioral performance, increasing rearing and ambulation by 3.2- and 2.6-fold, novel object exploration by 2.4-fold, and target quadrant time by 1.7-fold compared to the 3-NP group. At the molecular level, ART reduced HMGB1 (69.2%), TLR4 (60.4%), RIPK1 (66.3%), RIPK3 (66.4%), MLKL (58%), and TNF-α (62.5%), while significantly restoring GSH (2.1-fold), Nrf2 (3.7-fold), Sig1R (5.2-fold), D2R (2.6-fold), XIAP (3.7-fold), BDNF (2.3-fold) and SDH (1.94-fold) relative to 3-NP-treated rats. Collectively, these results demonstrate that ART confers robust neuroprotection against 3-NP-induced HD-like pathology by attenuating oxidative stress, suppressing HMGB1/TLR4/NF-κB signaling, inhibiting necroptosis, and upregulating neuroprotective markers. These findings highlight ART not only as a neuroprotective agent but also as a promising symptom-attenuating therapeutic candidate for Huntington’s disease and other neurodegenerative disorders driven by oxidative and inflammatory stress.</p></div>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":"49 3","pages":"375 - 392"},"PeriodicalIF":7.5,"publicationDate":"2026-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s12272-026-01604-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147497601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nanostructured branched Y-DNA promotes antitumor immunity through dual activation of cGAS/STING and TLR9","authors":"Jin Kyung Seok,&nbsp;Jung In Jee,&nbsp;Jong Han Oh,&nbsp;So Yeon Ahn,&nbsp;Hana Cho,&nbsp;Young Eun Yang,&nbsp;Minhyuk Kim,&nbsp;Hyung-Joo Kwon,&nbsp;Yong-Yeon Cho,&nbsp;Hye Suk Lee,&nbsp;Soong Ho Um,&nbsp;Han Chang Kang,&nbsp;Joo Young Lee","doi":"10.1007/s12272-026-01607-y","DOIUrl":"10.1007/s12272-026-01607-y","url":null,"abstract":"<div><p>Effective activation of innate and adaptive immunity remains a major challenge in cancer immunotherapy. In this study, we aimed to develop an immunostimulatory oligonucleotides for antitumor immunotherapy. We designed branched Y-shaped DNA (Yb-DNA) nanoparticles complexed with a reducible polycationic carrier (RPC-bPEI_0.8kDa), which we named YbNano, to enhance intracellular delivery and immune activation. The immunostimulatory activity of YbNano was determined in mouse bone marrow-derived dendritic cells. The efficacy of YbNano for antitumor immunotherapy was investigated using a melanoma allograft mouse model and a lung metastasis of breast cancer mouse model. YbNano exhibited uniform particle morphology and efficient cellular uptake in dendritic cells. YbNano induced robust expression of type I interferon (IFN-β), interleukin-12 (IL-12), chemokines such as CXCL10, and costimulatory molecules (CD80, CD86) in dendritic cells, promoting CD8⁺ T cell differentiation. In preclinical cancer models, intravenous administration of YbNano potentiated the efficacy of anti-PD-L1 therapy in B16F10 melanoma-bearing C57BL/6 mice and enhanced the therapeutic outcomes of doxorubicin or anti-PD-L1 treatment in suppressing lung metastasis in 4T1 breast cancer-bearing BALB/c mice. YbNano functions as a dual activator of cGAS/STING and TLR9, orchestrating dendritic cell activation and amplifying downstream innate and adaptive immune responses in tumor microenvironment. Collectively, these findings suggest that YbNano represents a rationally engineered, multifunctional nucleic acid-based immunotherapeutic agent with the potential to modulate the tumor microenvironment and to augment responses when used in combination cancer therapy.</p></div>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":"49 3","pages":"321 - 338"},"PeriodicalIF":7.5,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s12272-026-01607-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147479860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanisms and structure–activity relationship of hypolipidemic effects of polysaccharides from natural resources: a review","authors":"Yao Wu,&nbsp;Yuying Zhang,&nbsp;Chuanming Gong,&nbsp;Bichang Fan,&nbsp;Shuying Li,&nbsp;Jiayi Zhang,&nbsp;Yuze Li,&nbsp;Xiaomei Song,&nbsp;Dongdong Zhang","doi":"10.1007/s12272-026-01603-2","DOIUrl":"10.1007/s12272-026-01603-2","url":null,"abstract":"<div><p>Hyperlipidemia, characterized by aberrant lipid metabolism, constitutes a pivotal risk factor for cardiovascular diseases (CVDs) and contributes to various metabolic complications. Although conventional lipid-lowering agents are widely used, their long-term clinical application is frequently constrained by adverse side effects. Consequently, natural polysaccharides have attracted significant attention as promising therapeutic candidates due to their potent hypolipidemic effects and favorable safety profiles. This review systematically elucidates the underlying mechanisms by which natural polysaccharides ameliorate hyperlipidemia. Furthermore, the structure–activity relationships (SAR) are critically examined, with particular emphasis on how physicochemical properties such as molecular weight, monosaccharide composition, and chemical modifications modulate biological activity. Finally, current limitations and major bottlenecks in existing research are discussed, and future perspectives are proposed. Collectively, this review provides a reference for the development of novel polysaccharide-based therapeutics for the management of hyperlipidemia.</p></div>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":"49 3","pages":"293 - 320"},"PeriodicalIF":7.5,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147479832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Homoharringtonine inhibits growth and migration in non-small cell lung cancer via PDIA4-mediated modulation of autophagy and EMT","authors":"Xiaoyu Ma,&nbsp;Panpan Lei,&nbsp;Bingxi Ren,&nbsp;Sifan Xie,&nbsp;Yuxiu Zhang,&nbsp;Yuanji Wang,&nbsp;Weina Ma","doi":"10.1007/s12272-026-01605-0","DOIUrl":"10.1007/s12272-026-01605-0","url":null,"abstract":"<div><p>Protein disulfide isomerase A4 (PDIA4) is overexpressed in non-small cell lung cancer (NSCLC) and is associated with poor prognosis. This study demonstrates that elevated PDIA4 expression promotes NSCLC progression, whereas its knockdown inhibits disease advancement, establishing PDIA4 as an oncogenic driver and potential biomarker. Homoharringtonine (HHT), a natural alkaloid with broad-spectrum antitumor activity, exhibits efficacy against NSCLC, but its underlying mechanism remains unclear. In this study, HHT markedly suppresses NSCLC growth and migration in a PDIA4-dependent manner. Mechanistically, HHT initiates autophagy by regulating the AMPK/mTOR signaling pathway, while blocking autophagic flux, leading to autophagosome accumulation and consequent inhibition of NSCLC growth. Additionally, HHT inhibits NSCLC migration by modulating epithelial-mesenchymal transition (EMT) signaling. These findings highlight PDIA4 as a critical mediator of HHT efficacy against NSCLC, provide novel insights into PDIA4-associated therapy, and support the translational potential of HHT in NSCLC treatment.</p></div>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":"49 3","pages":"357 - 374"},"PeriodicalIF":7.5,"publicationDate":"2026-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147454817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"P7C3 alleviates hepatic fibrosis via targeting eIF4A1-mediated protein translation and autophagy in hepatic stellate cells","authors":"Ailing Liang,&nbsp;Ling Yao,&nbsp;Yuanyuan Liu,&nbsp;Honglin He,&nbsp;Yao Lei,&nbsp;Yunheng Yang,&nbsp;Jun Liu,&nbsp;Jiamei Yu,&nbsp;Weiguo Cao,&nbsp;Zhiwei Chen","doi":"10.1007/s12272-026-01602-3","DOIUrl":"10.1007/s12272-026-01602-3","url":null,"abstract":"<div><p>P7C3, an aminopropyl carbazole compound with established neuroprotective properties and therapeutic potential in neurodegenerative disorders, has demonstrated broad pharmacological activity across multiple pathologies. However, the effect of P7C3 on hepatic fibrosis remains unexplored. This research applied in vitro and in vivo systems to evaluate P7C3’s antifibrotic efficacy. The findings demonstrated that P7C3 notably inhibited the proliferation of LX-2 cells and activated primary hepatic stellate cells (HSCs), while also reducing levels of the fibrotic markers collagen type alpha 1 (COL1A1) and fibronectin (FN). Eukaryotic initiation factor 4A1 (eIF4A1) was identified as a direct target of P7C3 through the integration of cellular thermal shift assay (CETSA) coupled with mass spectrometry and human protein microarray data, and subsequently validated using CETSA, drug affinity responsive target stability, and molecular docking analysis. eIF4A1 expression was higher in activated primary HSCs than in quiescent cells. P7C3 treatment markedly inhibited eIF4A1 levels in LX-2 cells and activated primary HSCs. eIF4A1 knockdown downregulated the expression of COL1A1 and FN, whereas its overexpression effectively reversed this suppression. Mechanistically, P7C3 impaired global protein synthesis in hepatic stellate cells, including c-Myc, consistent with the outcomes observed following eIF4A1 silencing. Both eIF4A1 knockdown and P7C3 treatment significantly downregulated ULK1, induced accumulation of autophagic substrate p62, and increased LC3B-II/LC3B-I ratio, indicating potent disruption of autophagic flux via eIF4A1 targeting. Histopathological assessment of the liver tissues revealed that P7C3 significantly attenuated collagen deposition and architectural distortion in fibrotic mice. Concomitant improvements were observed in the hepatic function biomarkers, including serum ALT and AST levels, as well as in fibrotic markers (hydroxyproline content). Collectively, these findings delineated eIF4A1 as the primary target through which P7C3 alleviates hepatic fibrosis by suppressing protein translation and autophagic flux, providing mechanistic validation for advancing it as a promising antifibrotic agent.</p></div>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":"49 2","pages":"262 - 277"},"PeriodicalIF":7.5,"publicationDate":"2026-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147316167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PBPK modeling of the antidepressant doxepin incorporating CYP2D6 genotype for precision pharmacotherapy","authors":"Joohee Seok,&nbsp;Nahyun Kang,&nbsp;Je Jin Lee,&nbsp;Chang-Keun Cho,&nbsp;Yun Jeong Lee","doi":"10.1007/s12272-026-01600-5","DOIUrl":"10.1007/s12272-026-01600-5","url":null,"abstract":"<div><p>Doxepin, a tricyclic antidepressant, exhibits substantial interindividual variability in pharmacokinetics, mainly attributable to genetic polymorphisms of cytochrome P450 (CYP) enzymes, particularly CYP2D6. Such variability may lead to clinically relevant differences in drug exposure, therapeutic response, and adverse effects when doxepin is used for antidepressant therapy. The present study aimed to develop and validate physiologically based pharmacokinetic (PBPK) models of doxepin and its active metabolite, <i>N</i>-desmethyldoxepin, incorporating CYP2D6 genetic polymorphisms to support precision pharmacotherapy. PBPK models were constructed using PK-Sim^® (version 12.0) based on published clinical pharmacokinetic and pharmacogenomic data obtained after oral administration of doxepin. Model development was performed in a non-genotyped population. Subsequently, it extended to CYP2D6 ultra-rapid (UM), normal (NM), intermediate (IM), and poor metabolizer (PM) phenotypes by integrating genotype-specific metabolic activity. Model performance was evaluated by comparing predicted plasma concentration–time profiles, area under the concentration–time curve (AUC), and maximum plasma concentration (C_max) with observed clinical data. The model's predictive capability was further assessed using goodness-of-fit analysis, visual predictive checks, and geometric mean fold error (GMFE). The PBPK models adequately reproduced the observed pharmacokinetics of doxepin and <i>N</i>-desmethyldoxepin, with most predicted AUC and C_max values falling within a twofold error range across both non-genotyped and CYP2D6-genotyped populations. Simulations demonstrated an apparent genotype-dependent increase in doxepin exposure as CYP2D6 metabolic capacity decreased, consistent with clinical observations. Similarly, <i>N</i>-desmethyldoxepin exposure showed an inverse relationship with CYP2D6 activity, reflecting differences in metabolite formation and elimination. Despite the limited availability of genotype-specific concentration–time data for the metabolite, the model captured observed exposure trends, supporting its mechanistic plausibility. In conclusion, a PBPK framework integrating CYP2D6 genetic polymorphisms was successfully developed for doxepin and its active metabolite. The model reliably predicts genotype-dependent pharmacokinetic variability and provides a mechanistic basis for individualized dose optimization. This PBPK approach may serve as a valuable tool to support precision pharmacotherapy for doxepin, particularly in the context of antidepressant treatment.</p></div>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":"49 2","pages":"278 - 291"},"PeriodicalIF":7.5,"publicationDate":"2026-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12999657/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147301487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuroinflammation and blood–brain barrier disruption in Japanese encephalitis virus infection: mechanisms, therapeutic targets, and intervention strategies","authors":"Xiaochun Ye,&nbsp;Ping Wang,&nbsp;Mengping Song,&nbsp;Jieying Zhang,&nbsp;Xiangmin Li,&nbsp;Xu Wang","doi":"10.1007/s12272-026-01598-w","DOIUrl":"10.1007/s12272-026-01598-w","url":null,"abstract":"<div><p>Japanese encephalitis virus (JEV), as a neurotropic flavivirus, remains a primary cause of viral encephalitis and poses a significant public health challenge. Its pathogenic mechanism centers on the pathological interaction between blood–brain barrier (BBB) disruption and uncontrolled neuroinflammation, which collectively promote JEV neuroinvasion and result in irreversible brain damage. Therefore, elucidating the molecular mechanisms by which JEV disrupts the BBB and induces neuroinflammation is crucial for developing novel therapeutic strategies. This paper systematically elucidates the mechanisms by which JEV induces BBB disruption and neuroinflammation, focusing on key viral and host factors. Furthermore, we summarize recent advances in innate immune responses during JEV infection and explore potential therapeutic strategies to alleviate neuroinflammation and restore BBB integrity. Finally, we explored key knowledge gaps, translational medicine challenges, and future research directions. Given the current lack of specific antiviral treatments, there is an urgent need to develop novel intervention approaches to improve clinical outcomes.</p></div>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":"49 2","pages":"197 - 222"},"PeriodicalIF":7.5,"publicationDate":"2026-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147275423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"JAK2/STAT3-dependent regulation of MDM4/MDM2-p53 signaling in methotrexate-induced ferroptosis and nephrotoxicity","authors":"Yu Cheng,&nbsp;Mingming Zhao,&nbsp;Yujia Zhang,&nbsp;Maobai Liu,&nbsp;Limei Zhao","doi":"10.1007/s12272-026-01599-9","DOIUrl":"10.1007/s12272-026-01599-9","url":null,"abstract":"<div><p>Methotrexate (MTX), a cornerstone therapeutic agent for malignancies and autoimmune diseases, is clinically constrained by its severe nephrotoxic effects. Although oxidative stress and apoptosis have been implicated in MTX-induced nephrotoxicity, the precise molecular mechanisms underlying this process remain incompletely characterized. This study investigates ferroptosis as a novel pathological contributor to MTX-induced nephrotoxicity and evaluates therapeutic interventions targeting the JAK2/STAT3-MDM4/MDM2 signaling axis. Through integrated approaches including RNA sequencing, lentiviral-mediated knockdown experiments (MTX: IC₂₀ 38 μM), and a rat model of MTX (20 mg/kg)-induced acute kidney injury, we demonstrated that MTX treatment upregulated MDM4 expression, activated the JAK2/STAT3 signaling pathway, and enhanced MDM4/MDM2 heterodimer formation, thereby suppressing p53 and contributing to ferroptotic cell death. Importantly, either the knockdown of <i>MDM4</i> or pharmacological inhibition of JAK2/STAT3 signaling pathway with JSI-124 partially attenuated MTX-induced ferroptosis, improved renal function indicators, and attenuated histopathological damage in vivo. Our findings demonstrate that MTX mediates phosphorylation-dependent activation of the JAK2/STAT3 pathway, which facilitates MDM4/MDM2 interaction to induce ferroptosis-associated nephrotoxicity. These findings support a role for JAK2/STAT3-MDM4/MDM2 signaling in MTX-induced ferroptosis and suggest that targeted inhibition of this axis may represent a potential nephroprotective strategy.</p></div>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":"49 2","pages":"223 - 241"},"PeriodicalIF":7.5,"publicationDate":"2026-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147269845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bispecific antibody–drug conjugates: a modular blueprint for next-generation cancer therapeutics","authors":"Yulin Bai,&nbsp;Huaqing Lei,&nbsp;Shuang Gou,&nbsp;Jiarui Lan,&nbsp;Dan Cai,&nbsp;Xin Zheng,&nbsp;Jing Shen,&nbsp;Yu Chen,&nbsp;Yueshui Zhao,&nbsp;Shuai Deng,&nbsp;Xu Wu,&nbsp;Mingxing Li,&nbsp;Zhangang Xiao,&nbsp;Yan Zhang,&nbsp;Fukuan Du","doi":"10.1007/s12272-026-01595-z","DOIUrl":"10.1007/s12272-026-01595-z","url":null,"abstract":"<div><p>Antibody–drug conjugates (ADCs) have rapidly developed over the past two decades as a class of targeted anticancer agents. These drugs deliver highly cytotoxic payloads conjugated to specific antibodies, targeting cancer cells and releasing the payload intracellularly to selectively kill tumor cells. However, in clinical practice, the therapeutic efficacy of ADCs is often inconsistent due to factors such as off-target effects, limited endocytosis rates, and the narrow specificity of the target. Bispecific antibody–drug conjugates (BsADCs) combine the characteristics of bispecific antibodies and ADCs, offering enhanced recognition capabilities and facilitating faster drug internalization, thereby potentially improving the therapeutic index and addressing some of the limitations of traditional ADCs. Moreover, BsADCs have the potential to treat not only cancer but also other diseases, positioning them as a future direction for ADC development.This review provides a brief overview of the structure of ADCs and current clinical research results. It focuses on the “toolbox” components of BsADCs and highlights examples of how each component is applied in the construction of BsADCs. This review also summarizes the key characteristics required for bispecific antibodies used in BsADC construction. Finally, a detailed analysis of the advantages of BsADCs over traditional ADCs is presented, along with a discussion of their future development. This paper aims to provide researchers interested in ADCs and BsADCs with detailed information on the composition, structure, and applications (including clinical data) of both ADCs and BsADCs, helping readers quickly understand the features and research progress of BsADCs and paving the way for further exploration in this field.</p></div>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":"49 1","pages":"61 - 100"},"PeriodicalIF":7.5,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146140961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of a potent STAT3 inhibitor WR-S-647 for the treatment of ADPKD","authors":"Zhaoyong Kang,&nbsp;Wenchao Zhao,&nbsp;Wangrui Jin,&nbsp;Yongzhan Sun,&nbsp;Yangrui Peng,&nbsp;Jiemin Wong,&nbsp;Dong Guo,&nbsp;Yihua Chen","doi":"10.1007/s12272-026-01594-0","DOIUrl":"10.1007/s12272-026-01594-0","url":null,"abstract":"<div><p>Autosomal dominant polycystic kidney disease (ADPKD) affects approximately 12.5 million individuals globally and is one of the most common causes of end-stage renal disease. It is typically associated with a gradual increase in the volume of numerous cysts in both kidneys. Recent studies have highlighted the critical role of signal transducer and activator of transcription 3 (STAT3) in ADPKD pathogenesis, as it is highly expressed and persistently activated in ADPKD kidneys. Through screening of our in-house compound library, we identified compound <b>WR-S-647</b> (<b>4e</b>) as a potent and specific inhibitor of STAT3 with a binding affinity of 34 nM to STAT3. <b>WR-S-647</b> suppressed the phosphorylation activation and nuclear localization of STAT3. In vitro, <b>WR-S-647</b> remarkably suppressed cyst formation and expansion in a Madin-Darby canine kidney (MDCK) cyst model. Meanwhile, it effectively diminished cyst growth in an ex vivo embryonal renal cyst model and an in vivo<i> Pkd1</i> knockout ADPKD mouse model. Our study identifies <b>WR-S-647</b> as a potent STAT3-mediated inhibitor and provides preclinical proof-of-concept for its efficacy in reducing cyst growth in ADPKD models.</p></div>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":"49 1","pages":"174 - 196"},"PeriodicalIF":7.5,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146112052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}