Acta Pharmaceutica Sinica. B最新文献

{"title":"Nanomedicine strategies for cuproptosis: Metabolic reprogramming and tumor immunotherapy","authors":"Ruixuan Zhang ,&nbsp;Yunfei Li ,&nbsp;Hui Fu ,&nbsp;Chengcheng Zhao ,&nbsp;Xiuyan Li ,&nbsp;Yuming Wang ,&nbsp;Yujiao Sun ,&nbsp;Yingpeng Li","doi":"10.1016/j.apsb.2025.07.007","DOIUrl":"10.1016/j.apsb.2025.07.007","url":null,"abstract":"<div><div>Cuproptosis, a recently discovered form of regulated cell death involving copper ion metabolism, has emerged as a promising approach for tumor therapy. This pathway not only directly eliminates tumor cells but also promotes immunogenic cell death (ICD), reshaping the tumor microenvironment (TME) and initiating robust anti-tumor immune responses. However, translating cuproptosis-based therapies into clinical applications is hindered by challenges, including complex metabolic regulation, TME heterogeneity, and the precision required for effective drug delivery. To address these limitations, nanoparticles offer transformative solutions by providing precise delivery of cuproptosis-inducing agents, controlled drug release, and enhanced therapeutic efficacy through simultaneous modulation of metabolic pathways and immune responses. This review systematically discusses recent advancements in nanoparticle-based cuproptosis delivery systems, highlighting nanoparticle design principles and their synergistic effects when integrated with other therapeutic modalities such as ICB, PTT, and CDT. Furthermore, we explore the potential of cuproptosis-based nanomedicine for personalized cancer treatment by emphasizing strategies for TME stratification and therapeutic optimization tailored to patient profiles. By integrating current insights from metabolic reprogramming, tumor immunotherapy, and nanotechnology, this review aims to facilitate the clinical translation of cuproptosis nanomedicine and significantly contribute to the advancement of precision oncology.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 9","pages":"Pages 4582-4613"},"PeriodicalIF":14.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145108384","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}

{"title":"Intercellular communication interference through energy metabolism-related exosome secretion inhibition for liver fibrosis treatment","authors":"Mengyao Zhang ,&nbsp;Huaqing Jing ,&nbsp;Xinyi Liu ,&nbsp;Valentin A. Milichko ,&nbsp;Yunsheng Dou ,&nbsp;Yingzi Ren ,&nbsp;Zitong Qiu ,&nbsp;Wen Li ,&nbsp;Weili Liu ,&nbsp;Xinxing Wang ,&nbsp;Nan Li","doi":"10.1016/j.apsb.2025.07.008","DOIUrl":"10.1016/j.apsb.2025.07.008","url":null,"abstract":"<div><div>As activated hepatic stellate cells (aHSCs) play a central role in fibrogenesis, they have become key target cells for anti-fibrotic treatment. Nevertheless, the therapeutic efficiency is constrained by the exosomes they secrete, which are linked to energy metabolism and continuously stimulate the activation of neighboring quiescent hepatic stellate cells (qHSCs). Herein, an intercellular communication interference strategy is designed utilizing paeoniflorin (PF) loaded and hyaluronic acid (HA) coated copper-doped ZIF-8 (PF@HA-Cu/ZIF-8, PF@HCZ) to reduce energy-related exosome secretion from aHSCs, thus preserving neighboring qHSCs in a quiescent state. Simultaneously, the released copper and zinc ions disrupt key enzymes involved in glycolysis to reduce bioenergy synthesis in aHSCs, thereby promoting the reversion of aHSCs to a quiescent state and further decreasing exosome secretion. Therefore, PF@HCZ can effectively sustain both aHSCs and qHSCs in a metabolically dormant state to ultimately alleviate liver fibrosis. The study provides an enlightening strategy for interrupting exosome-mediated intercellular communication and remodeling the energy metabolic status of HSCs with boosted antifibrogenic activity.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 9","pages":"Pages 4900-4916"},"PeriodicalIF":14.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145099992","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}

{"title":"Metallic nanomedicine in cancer immunotherapy","authors":"Shixuan Li ,&nbsp;Xiaohu Wang ,&nbsp;Huiyun Han ,&nbsp;Shuting Xiang ,&nbsp;Mingxi Li ,&nbsp;Guangyu Long ,&nbsp;Yanming Xia ,&nbsp;Qiang Zhang ,&nbsp;Suxin Li","doi":"10.1016/j.apsb.2025.07.017","DOIUrl":"10.1016/j.apsb.2025.07.017","url":null,"abstract":"<div><div>Immunotherapy has become a pivotal modality in clinical cancer treatment. However, its effectiveness is limited to a small subset of patients due to the low antigenicity, impaired innate response, and various adaptive immune resistance mechanisms of the tumor microenvironment (TME). Accumulating evidence reveals the critical roles of metal elements in shaping immunity against tumor progression and metastasis. The marriage of metalloimmunotherapy and nanotechnology further presents new opportunities to optimize the physicochemical and pharmacokinetic properties of metal ions in a precise spatiotemporal control manner. Several metallodrugs have demonstrated encouraging immunotherapeutic potential in preliminary studies and are currently undergoing clinical trials at different stages, yet challenges persist in scaling up production and addressing long-term biosafety concerns. This review delineates how metal materials modulate biological activities across diverse cell types to orchestrate antitumor immunity. Moreover, it summarizes recent progress in smart drug delivery-release systems integrating metal elements, either as cargo or vehicles, to enhance antitumor immune responses. Finally, the review introduces current clinical applications of nanomedicines in metalloimmunotherapy and discusses potential challenges that impede its widespread translation into clinical practice.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 9","pages":"Pages 4614-4643"},"PeriodicalIF":14.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145108350","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}

{"title":"The role of SARS-CoV-2 main protease in innate immune regulation: From molecular mechanisms to therapeutic implications","authors":"Yumeng Gao,&nbsp;Jun Zhang","doi":"10.1016/j.apsb.2025.07.001","DOIUrl":"10.1016/j.apsb.2025.07.001","url":null,"abstract":"<div><div>The main protease (M^pro) of SARS-CoV-2 plays a pivotal role in viral replication and immune evasion. Accumulating evidence highlights its significant role in suppressing innate immunity. In this review, we provide a comprehensive overview of how M^pro modulates host innate immune responses, including its interference with retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) and cyclic GMP–AMP synthase (cGAS)–stimulator of interferon gene (STING) signaling pathways, inhibition of interferon production, and disruption of inflammasome activities. As a protease, M^pro cleaves a variety of host proteins to attenuate antiviral innate immunity, a process dependent on its catalytic dyad (Cys145–His41), which is crucial for its proteolytic activity. Meanwhile, M^pro also exerts innate immune regulatory functions in a protease-independent manner. Notably, inhibitors targeting M^pro have demonstrated efficacy in restoring immune functions and suppressing viral replication, offering potential therapeutic strategies against SARS-CoV-2 infection.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 9","pages":"Pages 4497-4510"},"PeriodicalIF":14.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145108380","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}

{"title":"From synaptic gatekeepers to affective-cognitive modulators: The astrocyte D1 receptor–d-serine axis in the prefrontal cortex","authors":"Li-Pao Fang ,&nbsp;Frank Kirchhoff","doi":"10.1016/j.apsb.2025.08.018","DOIUrl":"10.1016/j.apsb.2025.08.018","url":null,"abstract":"","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 9","pages":"Pages 4967-4969"},"PeriodicalIF":14.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145108256","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}

{"title":"Biased signaling via serotonin 5-HT2A receptor: From structural aspects to in vitro and in vivo pharmacology","authors":"Michał K. Jastrzębski ,&nbsp;Piotr Wójcik ,&nbsp;Angelika Grudzińska ,&nbsp;Giorgia Andreozzi ,&nbsp;Tommaso Vetrò ,&nbsp;Ayesha Asim ,&nbsp;Akanksha Mudgal ,&nbsp;Jakub Czapiński ,&nbsp;Tomasz M. Wróbel ,&nbsp;Damian Bartuzi ,&nbsp;Katarzyna M. Targowska-Duda ,&nbsp;Agnieszka A. Kaczor","doi":"10.1016/j.apsb.2025.07.002","DOIUrl":"10.1016/j.apsb.2025.07.002","url":null,"abstract":"<div><div>G protein-coupled receptors (GPCRs) represent key drug targets, with approximately 30%–40% of all medications acting on these receptors. Recent advancements have uncovered the complexity of GPCR signaling, including biased signaling, which allows selective activation of specific intracellular pathways—primarily mediated by G proteins and <em>β</em>-arrestins. Among aminergic GPCRs, the serotonin 5-HT_2A receptor has garnered attention for its potential to generate therapeutic effects without adverse outcomes, such as hallucinations, through biased agonism. This review delivers a comprehensive overview of 5-HT_2A receptor-biased signaling and its significance in developing safer mental health therapeutics, particularly for depression and anxiety. We provide a critical evaluation of methodologies for assessing biased signaling, spanning from traditional radioligand binding assays to advanced biosensor technologies. Furthermore, we review structural studies and computational modeling that have identified key receptor residues modulating biased signaling. We also highlight novel biased ligands with selective pathway activation, presenting a promising avenue for developing targeted antidepressant therapies without psychedelic effects. Additionally, we explore the 5-HT_2A receptor's role in memory processes and stress response regulation. Ultimately, advancing our understanding of 5-HT_2A receptor-biased signaling could drive the development of next-generation GPCR-targeted therapies, maximizing therapeutic efficacy while minimizing side effects in psychiatric treatment.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 9","pages":"Pages 4438-4455"},"PeriodicalIF":14.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145108378","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}

{"title":"Immunoregulatory mechanisms in the aging microenvironment: Targeting the senescence-associated secretory phenotype for cancer immunotherapy","authors":"Haojun Wang ,&nbsp;Yang Yu ,&nbsp;Runze Li ,&nbsp;Huiru Zhang ,&nbsp;Zhe-sheng Chen ,&nbsp;Changgang Sun ,&nbsp;Jing Zhuang","doi":"10.1016/j.apsb.2025.07.022","DOIUrl":"10.1016/j.apsb.2025.07.022","url":null,"abstract":"<div><div>The aging microenvironment, as a key driver of tumorigenesis and progression, plays a critical role in tumor immune regulation through one of its core features—the senescence-associated secretory phenotype (SASP). SASP consists of a variety of interleukins, chemokines, proteases, and growth factors. It initially induces surrounding cells to enter a state of senescence through paracrine mechanisms, thereby creating a sustained inflammatory stimulus and signal amplification effect within the tissue microenvironment. Furthermore, these secreted factors activate key signaling pathways such as NF-<em>κ</em>B, cGAS–STING, and mTOR, which regulate the expression of immune-related molecules (such as PD-L1) and promote the recruitment of immunosuppressive cells, including regulatory T cells and myeloid-derived suppressor cells. This process ultimately contributes to the formation of an immunosuppressive tumor microenvironment. Furthermore, the article explores potential anti-tumor immunotherapy strategies targeting SASP and its associated molecular mechanisms, including approaches to inhibit SASP secretion or eliminate senescent cells. Although these strategies have shown promise in certain tumor models, the high heterogeneity among tumor types may result in varied responses to SASP-targeted therapies. This highlights the need for further research into adaptive stratification and personalized treatment approaches. Targeting immune regulatory mechanisms in the aging microenvironment—particularly SASP—holds great potential for advancing future anti-tumor therapies.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 9","pages":"Pages 4476-4496"},"PeriodicalIF":14.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145108379","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}

{"title":"Astrocyte FGF7/FGFR2 autocrine signaling mediates neuroinflammation and promotes MPTP-induced degeneration of dopaminergic neurons","authors":"Xin Sun ,&nbsp;Yueping Wang ,&nbsp;Yajie Zhang ,&nbsp;Ruixue Han ,&nbsp;Min Wang ,&nbsp;Jing Zhang ,&nbsp;Ting Sun ,&nbsp;Yang Liu ,&nbsp;Gang Hu ,&nbsp;Lei Cao ,&nbsp;Ming Lu","doi":"10.1016/j.apsb.2025.07.012","DOIUrl":"10.1016/j.apsb.2025.07.012","url":null,"abstract":"<div><div>Reactive astrocytes, which exhibit a correlation with the degeneration of dopaminergic neurons, are present in a considerable number during the progression of Parkinson's disease (PD). However, the underlying factors shaping astrocyte reactivity and neuroinflammation in PD remain inadequately elucidated. Here, we demonstrate that fibroblast growth factor 7 (FGF7)/FGF receptor 2 (FGFR2) autocrine signaling intensifies astrocyte reactivity and inflammation. Genetic deletion of <em>Arrb2</em>, <em>β</em>-Arrestin2 encoding gene, led to escalated astrocyte reactivity in MPTP-treated mice, which was further substantiated in astrocyte-specific <em>Arrb2</em> knockdown mice. RNA sequencing profiling of <em>Arrb2</em> knockout astrocytes identified <em>Fgf7</em> as a critical effector of astrocyte reactivity. Subsequently, conditional knockdown of <em>Fgf7</em> and its receptor <em>Fgfr2</em> in astrocytes elicited advantageous effects for MPTP-treated mice by restraining the inflammatory phenotypic transition of reactive astrocytes. Furthermore, deletion of astrocytic <em>Fgf7</em> mitigated MPTP-induced pathology in <em>Arrb2</em> knockout mice. Mechanistically, STAT1 was distinguished as the transcription factor suppressing <em>Fgf7</em> expression, while <em>β</em>-Arrestin2 counteracted the proteasomal degradation of STAT1 by binding to RNF220, an E3 ubiquitin ligase for STAT1. More importantly, selectively engaging dopamine D2 receptor (Drd2)/<em>β</em>-Arrestin2-biased signaling using the agonist UNC9995 exhibited therapeutic potential in MPTP-treated mice <em>via</em> moderation of astrocytic FGF7 production, thereby restoring balance in astrocyte reactivity. Collectively, our study bridges a crucial knowledge gap by elucidating the novel functions of FGF family members within the central nervous system, particularly within the context of PD. The autocrine signaling of FGF7/FGFR2 represents a novel mechanism and a potential druggable target for modulating astrocyte-derived inflammation.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 9","pages":"Pages 4730-4750"},"PeriodicalIF":14.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145108341","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}

{"title":"Next-generation antifungal drugs: Mechanisms, efficacy, and clinical prospects","authors":"Xueni Lu ,&nbsp;Jianlin Zhou ,&nbsp;Yi Ming ,&nbsp;Yuan Wang ,&nbsp;Ruirui He ,&nbsp;Yangyang Li ,&nbsp;Lingyun Feng ,&nbsp;Bo Zeng ,&nbsp;Yanyun Du ,&nbsp;Chenhui Wang","doi":"10.1016/j.apsb.2025.06.013","DOIUrl":"10.1016/j.apsb.2025.06.013","url":null,"abstract":"<div><div>Invasive fungal infections (IFIs) have become prominent global health threats, escalating the burden on public health systems. The increasing occurrence of invasive fungal infections is due primarily to the extensive application of chemotherapy, immunosuppressive therapies, and broad-spectrum antifungal agents. At present, therapeutic practices utilize multiple categories of antifungal agents, such as azoles, polyenes, echinocandins, and pyrimidine analogs. Nevertheless, the clinical effectiveness of these treatments is progressively weakened by the emergence of drug resistance, thereby substantially restricting their therapeutic utility. Consequently, there is an imperative need to expedite the discovery of novel antifungal agents. This review seeks to present an exhaustive synthesis of novel antifungal drugs and candidate agents that are either under current clinical investigation or anticipated to progress into clinical evaluation. These emerging compounds exhibit unique benefits concerning their modes of action, antimicrobial spectra, and pharmacokinetic characteristics, potentially leading to improved therapeutic outcomes relative to conventional antifungal regimens. It is anticipated that these novel therapeutic agents will furnish innovative treatment modalities and enhance clinical outcomes in managing invasive fungal infections.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 8","pages":"Pages 3852-3887"},"PeriodicalIF":14.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144863333","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}

{"title":"Blades and barriers: Oral vaccines for conquering cancers and warding off infectious diseases","authors":"Kun Yang ,&nbsp;Jinhua Liu ,&nbsp;Yi Zhao ,&nbsp;Haiting Xu ,&nbsp;Menghang Zu ,&nbsp;Baoyi Li ,&nbsp;Xiaoxiao Shi ,&nbsp;Rui L. Reis ,&nbsp;Subhas C. Kundu ,&nbsp;Bo Xiao","doi":"10.1016/j.apsb.2025.05.038","DOIUrl":"10.1016/j.apsb.2025.05.038","url":null,"abstract":"<div><div>Global public health faces substantial challenges from malignant tumors and infectious diseases. Vaccination provides an approach for treating and preventing these diseases. Oral vaccinations are particularly advantageous in disease treatment and prevention due to their non-invasive nature, high patient compliance, convenience, cost-effectiveness, and capacity to stimulate comprehensive and adaptive immune responses. However, the overwhelming majority of oral vaccines remain in experimental development, struggling with clinical and commercial translation due to their suboptimal efficacy. Thus, enhancing scientists’ understanding of the interaction between vaccines and gastrointestinal immune system, creating antigen delivery systems suitable for the gut mucosal environment, developing more potent antigenic epitopes, and using personalized combination therapies are critical for advancing the next generation of oral vaccines. This article explores the fundamental principles and applications of current oral anti-tumor and anti-infective vaccines and discusses considerations necessary for designing future oral vaccines.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 8","pages":"Pages 3925-3950"},"PeriodicalIF":14.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144863335","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}