Acta Pharmaceutica Sinica. B最新文献

{"title":"Protein palmitoylation: A potential therapeutic target in cardiovascular diseases","authors":"Sijia Zhao ,&nbsp;Yanyan Yang ,&nbsp;Hong Li ,&nbsp;Pin Sun ,&nbsp;Xiangqin He ,&nbsp;Chao Wang ,&nbsp;Jingjing Zhang ,&nbsp;Yu Tian ,&nbsp;Tao Yu ,&nbsp;Zhirong Jiang","doi":"10.1016/j.apsb.2025.07.041","DOIUrl":"10.1016/j.apsb.2025.07.041","url":null,"abstract":"<div><div>Palmitoylation, an essential covalent attachment of a fatty acid (usually C16 palmitate) to cysteine residues within proteins, is crucial for regulating protein functionality and enzymatic activities. This lipid modification facilitates the anchoring of proteins to cellular membranes, dictating their subcellular distribution and influencing protein transport dynamics and intracellular positioning. Additionally, it plays a role in regulating protein degradation through the ubiquitin-proteasome system. Palmitoylation is implicated in the pathogenesis and progression of cardiovascular diseases by modulating substrates and prompting additional post-translational modifications, as well as by interacting with other molecular alterations. Moreover, an intervention strategy focusing on palmitoylation processes is anticipated to offer novel therapeutic avenues for cardiovascular pathologies and address extant challenges in clinical settings. This review consolidates current research on the role and importance of palmitoylation in cardiovascular diseases by exploring its regulatory functions, the catalyzing enzymes, and the involved substrates. It highlights recent discoveries connecting palmitoylation-targeted therapies to cardiovascular health and examines potential approaches and future challenges in cardiovascular treatment.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 10","pages":"Pages 5127-5144"},"PeriodicalIF":14.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229929","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":"A dual-targeting peptide–drug conjugate based on CXCR4 and FOLR1 inhibits triple-negative breast cancer","authors":"Kun Wang ,&nbsp;Cong Wang ,&nbsp;Hange Yang ,&nbsp;Gong Chen ,&nbsp;Ke Wang ,&nbsp;Peihong Ji ,&nbsp;Xudong Sun ,&nbsp;Xuegong Fan ,&nbsp;Jie Ma ,&nbsp;Zhencun Cui ,&nbsp;Xingkai Wang ,&nbsp;Hao Tian ,&nbsp;Dengfu Wu ,&nbsp;Lu Wang ,&nbsp;Zhimin Wang ,&nbsp;Jiangyan Liu ,&nbsp;Juan Yi ,&nbsp;Kuan Hu ,&nbsp;Hailong Zhang ,&nbsp;Rui Wang","doi":"10.1016/j.apsb.2025.06.012","DOIUrl":"10.1016/j.apsb.2025.06.012","url":null,"abstract":"<div><div>Triple-negative breast cancer is therapeutically challenging due to the low expression of tumor markers and ‘cold’ tumor immunosuppressive microenvironment. Here, we present a dual-targeting peptide–drug conjugate (PDC) for tumor inhibition. Our PDC efficiently and selectively delivers cytotoxic Monomethyl Auristatin E (MMAE) into tumor cells <em>via</em> C–X–C chemokine receptor type 4 (CXCR4) and folate receptor 1 (FOLR1) for synergistic inhibition of growth and metastasis. Our results show that the dual-targeting PDC has potent antitumor activity in cultured human cells and several murine transplanted tumor models without apparent toxicity. The combination of dual-targeting PDC and radiotherapy modulates the tumor immunosuppressive microenvironment by increasing CD8⁺ T cell infiltration and attenuating the proportion of myeloid-derived suppressor and regulatory T cells. Therefore, our dual-targeting PDC represents a promising new strategy for cancer therapy that rebalances the immune system and promotes tumor regression.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 10","pages":"Pages 4995-5009"},"PeriodicalIF":14.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229980","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":"Dissecting the effects of 223Radium on the bone microenvironment","authors":"Sergio Barrios ,&nbsp;Elisa Serafini ,&nbsp;Ludovica La Posta ,&nbsp;D. Nicole Meyers ,&nbsp;Nicholas J. Dunbar ,&nbsp;Paul G. Corn ,&nbsp;Florent Elefteriou ,&nbsp;Catherine G. Ambrose ,&nbsp;Stefano Casarin ,&nbsp;Antonios G. Mikos ,&nbsp;Eleonora Dondossola","doi":"10.1016/j.apsb.2025.07.035","DOIUrl":"10.1016/j.apsb.2025.07.035","url":null,"abstract":"<div><div>Radium-223 (²²³Ra) is a bone-seeking, alpha-particle-emitting radionuclide that is approved for the treatment of patients with metastatic prostate cancer and is currently being tested in clinical trials for primary and metastatic cancers to the bone. ²²³Ra accumulates in mineralized bone areas with high bone turnover, where its effects are confined within 100 μm of the bone–marrow interface due to the short tissue penetrance of the alpha particles. A recent clinical study has shown a significantly increased fracture rate associated with the administration of ²²³Ra, mostly in tumor-free bones. Importantly, the biological mechanisms underlying this bone fragility remain unclear. In this work, we combined micro-computed tomography and mechanical studies with <em>ex vivo</em> spatial biology analysis based on 3D fluorescence microscopy to clarify the effects of ²²³Ra on bone and key bone stromal cell components. We found that ²²³Ra caused major trabecular bone loss with no detectable impact on cortical bone. In addition, ²²³Ra impaired osteoblast bone-forming activity, which was paralleled by a transient increase in osteoclast number and long-term adipocyte formation. Overall, these results suggest that the impact of ²²³Ra on bone health is orchestrated by multiple bone stromal cell components. ²²³Ra-mediated trabecular bone loss was prevented by administration of zoledronic acid, which should always be combined with ²²³Ra.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 10","pages":"Pages 5010-5021"},"PeriodicalIF":14.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229981","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":"Cover Story","authors":"","doi":"10.1016/S2211-3835(25)00584-2","DOIUrl":"10.1016/S2211-3835(25)00584-2","url":null,"abstract":"","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 10","pages":"Page xiv"},"PeriodicalIF":14.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229978","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":"Discovery and proof-of-concept study of a novel highly selective sigma-1 receptor agonist for antipsychotic drug development","authors":"Wanyu Tang ,&nbsp;Zhixue Ma ,&nbsp;Bang Li ,&nbsp;Zhexiang Yu ,&nbsp;Xiaobao Zhao ,&nbsp;Huicui Yang ,&nbsp;Jian Hu ,&nbsp;Sheng Tian ,&nbsp;Linghan Gu ,&nbsp;Jiaojiao Chen ,&nbsp;Xing Zou ,&nbsp;Qi Wang ,&nbsp;Fan Chen ,&nbsp;Guangying Li ,&nbsp;Chaonan Zheng ,&nbsp;Shuliu Gao ,&nbsp;Wenjing Liu ,&nbsp;Yue Li ,&nbsp;Wenhua Zheng ,&nbsp;Mingmei Wang ,&nbsp;Xuechu Zhen","doi":"10.1016/j.apsb.2025.04.028","DOIUrl":"10.1016/j.apsb.2025.04.028","url":null,"abstract":"<div><div>Sigma-1 receptor (<em>σ</em>₁R) has become a focus point of drug discovery for central nervous system (CNS) diseases. A series of novel 1-phenylethan-1-one <em>O</em>-(2-aminoethyl) oxime derivatives were synthesized. <em>In vitro</em> biological evaluation led to the identification of <strong>1a</strong>, <strong>14a</strong>, <strong>15d</strong> and <strong>16d</strong> as the most high-affinity (<em>K</em>_i &lt; 4 nmol/L) and selective <em>σ</em>₁R agonists. Among these, <strong>15d</strong>, the most metabolically stable derivative exhibited high selectivity for <em>σ</em>₁R in relation to <em>σ</em>₂R and 52 other human targets. In addition to low CYP450 inhibition and induction, <strong>15d</strong> also exhibited high brain permeability and excellent oral bioavailability. Importantly, <strong>15d</strong> demonstrated effective antipsychotic potency, particularly for alleviating negative symptoms and improving cognitive impairment in experimental animal models, both of which are major challenges for schizophrenia treatment. Moreover, <strong>15d</strong> produced no significant extrapyramidal symptoms, exhibiting superior pharmacological profiles in relation to current antipsychotic drugs. Mechanistically, <strong>15d</strong> inhibited GSK3<em>β</em> and enhanced prefrontal BDNF expression and excitatory synaptic transmission in pyramidal neurons. Collectively, these <em>in vivo</em> proof-of-concept findings provide substantial experimental evidence to demonstrate that modulating <em>σ</em>₁R represents a potential new therapeutic approach for schizophrenia. The novel chemical entity along with its favorable drug-like and pharmacological profile of <strong>15d</strong> renders it a promising candidate for treating schizophrenia.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 10","pages":"Pages 5346-5365"},"PeriodicalIF":14.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229907","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":"A novel chemoreactive calcilytic for the potential treatment of autosomal dominant hypocalcemia","authors":"Jesse Dangerfield ,&nbsp;Aaron DeBono ,&nbsp;Andrew N. Keller ,&nbsp;Tracy M. Josephs ,&nbsp;David M. Shackleford ,&nbsp;Karen J. Gregory ,&nbsp;Katie Leach ,&nbsp;Ben Capuano","doi":"10.1016/j.apsb.2025.07.044","DOIUrl":"10.1016/j.apsb.2025.07.044","url":null,"abstract":"<div><div>Autosomal dominant hypocalcemia (ADH) type 1 and 2 are disorders of calcium homeostasis caused by gain of function variants. The calcium-sensing receptor (CaSR) is a class C GPCR that responds to elevated extracellular calcium (Ca²⁺_o) by inhibiting parathyroid hormone (PTH) secretion and promoting renal excretion of Ca²⁺ and other salts to restore physiologically normal Ca²⁺_o concentrations. CaSR negative allosteric modulators (NAMs) transiently raise PTH levels in individuals with ADH1, restoring Ca²⁺_o concentration to a physiological normal range. Herein we disclose the discovery of a chemoreactive NAM (ATF936-NCS, <strong>4</strong>) for the CaSR that (i) is wash-resistant indicative of irreversible receptor binding and (ii) stimulates prolonged PTH release <em>in vivo</em>. This ‘first-in-class’ chemical probe will provide invaluable insight towards the development of longer acting NAMs for the treatment of ADH.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 10","pages":"Pages 5387-5399"},"PeriodicalIF":14.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229909","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":"Targeted delivery of BMPR2 mRNA attenuates pulmonary arterial hypertension by reversing pulmonary vascular remodeling","authors":"Yan Cao ,&nbsp;Runyuan Wang ,&nbsp;Xiaoyan He ,&nbsp;Yan Ding ,&nbsp;Yan Chang ,&nbsp;Runyue Yang ,&nbsp;Guisheng Zhong ,&nbsp;Huiying Yang ,&nbsp;Jianfeng Li","doi":"10.1016/j.apsb.2025.07.004","DOIUrl":"10.1016/j.apsb.2025.07.004","url":null,"abstract":"<div><div>Disrupted bone morphogenetic protein type 2 receptor (BMPR2) signaling in endothelial cells drives pulmonary arterial hypertension (PAH). However, targeted recovery of this signaling pathway by lipid nanoparticles (LNPs) has not been explored as a therapy. Here, we employed Design of Experiments to optimize the delivery efficiency of LNPs targeting pulmonary endothelial cells developed by our laboratory, resulting in a remarkable 35-fold increase in a simplified three-component formulation without helper lipids. Administration of <em>BMPR2</em> mRNA LNPs effectively reversed established PAH in two experimental rat models (monocrotaline or SU5416-hypoxia) by reversing pulmonary vascular remodeling. Specifically, <em>BMPR2</em> mRNA LNPs replenished the expression of BMPR2 protein and subsequently activated downstream pathways, as confirmed by elevated levels of <em>p</em>-SMAD1/5/9 and ID1 proteins. The relief of pulmonary arterial occlusion was demonstrated by thinned pulmonary arterial media and decreased proportion of full muscularized vessels. Alleviation of right ventricular hypertrophy was indicated by declined Fulton index, the cross-sectional area of right ventricular cardiomyocytes as well as collagen deposition. Effective recovery of right ventricular function was evidenced by increased pulmonary artery flow acceleration time/pulmonary artery flow ejection time ratio. These findings underscore the potential of restoring BMPR2 signaling through pulmonary endothelial cell-specific LNPs for treating PAH.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 10","pages":"Pages 5416-5430"},"PeriodicalIF":14.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229911","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":"mRNA display-enabled discovery of proximity-triggered covalent peptide–drug conjugates","authors":"Ruixuan Wang ,&nbsp;Siqi Ran ,&nbsp;Jiabei Guo ,&nbsp;Da Hu ,&nbsp;Xiang Feng ,&nbsp;Jixia zhou ,&nbsp;Zhanzhi Zhang ,&nbsp;Futian Liang ,&nbsp;Jiamin Shang ,&nbsp;Lingxin Bu ,&nbsp;Kaiyi Wang ,&nbsp;Junyi Mao ,&nbsp;Huixin Luo ,&nbsp;Rui Wang","doi":"10.1016/j.apsb.2025.07.029","DOIUrl":"10.1016/j.apsb.2025.07.029","url":null,"abstract":"<div><div>Peptide–drug conjugates (PDCs) have emerged as a promising modality in precision oncology, enabling targeted delivery of cytotoxic payloads while minimizing off-target toxicity. The integration of covalent warheads, such as those based on sulfur(VI) fluoride exchange (SuFEx) chemistry, enhances drug–target residence time and tumor accumulation. However, existing screening methods for covalent peptide (CP) libraries require post-translational warhead conjugation, limiting throughput. Here, we present an integrated mRNA display platform that incorporates covalent warheads during ribosomal synthesis, enabling efficient screening of ultra-diverse covalent macrocyclic peptide libraries (&gt;10¹³ variants). This approach, using site-specific incorporation of <em>N-</em>chloroacetyl-<span>d</span>-phenylalanine and fluorosulfate-<span>l</span>-tyrosine, accelerated the discovery of irreversibly binding (<em>K</em>_i = 3.58 μmol/L) Nectin-4-targeting peptide CP-N1-N₃ <em>via</em> proximity-triggered SuFEx. The peptide was further conjugated to cytotoxic payloads, yielding the covalent PDC CP-N1-MMAE with potent cytotoxicity (IC₅₀ ≈ 43 nmol/L) against MDA-MB-468 cells. This platform establishes a new paradigm for precision covalent drug discovery.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 10","pages":"Pages 5474-5485"},"PeriodicalIF":14.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229916","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":"A preclinical and first-in-human study of superstable homogeneous radiolipiodol for revolutionizing interventional diagnosis and treatment of hepatocellular carcinoma","authors":"Hu Chen ,&nbsp;Yongfu Xiong ,&nbsp;Minglei Teng ,&nbsp;Yesen Li ,&nbsp;Deliang Zhang ,&nbsp;Yongjun Ren ,&nbsp;Zheng Li ,&nbsp;Hui Liu ,&nbsp;Xiaofei Wen ,&nbsp;Zhenjie Li ,&nbsp;Yang Zhang ,&nbsp;Syed Faheem Askari Rizvi ,&nbsp;Rongqiang Zhuang ,&nbsp;Jinxiong Huang ,&nbsp;Suping Li ,&nbsp;Jingsong Mao ,&nbsp;Hongwei Cheng ,&nbsp;Gang Liu","doi":"10.1016/j.apsb.2025.02.021","DOIUrl":"10.1016/j.apsb.2025.02.021","url":null,"abstract":"<div><div>Transarterial radioembolization (TARE) is a widely utilized therapeutic approach for hepatocellular carcinoma (HCC), however, the clinical implementation is constrained by the stringent preparation conditions of radioembolization agents. Herein, we incorporated the superstable homogeneous iodinated formulation technology (SHIFT), simultaneously utilizing an enhanced solvent form in a carbon dioxide supercritical fluid environment, to encapsulate radionuclides (such as ¹³¹I,¹⁷⁷Lu, or ¹⁸F) with lipiodol for the preparation of radiolipiodol. The resulting radiolipiodol exhibited exceptional stability and ultra-high labeling efficiency (≥99%) and displayed notable intratumoral radionuclide retention and <em>in vivo</em> stability more than 2 weeks following locoregional injection in subcutaneous tumors in mice and orthotopic liver tumors in rats and rabbits. Given these encouraging findings, ¹⁸F was authorized as a radiotracer in radiolipiodol for clinical trials in HCC patients, and showed a favorable tumor accumulation, with a tumor-to-liver uptake ratio of ≥50 and minimal radionuclide leakage, confirming the feasibility of SHIFT for TARE applications. In the context of transforming from preclinical to clinical screening, the preparation of radiolipiodol by SHIFT represents an innovative physical strategy for radionuclide encapsulation. Hence, this work offers a reliable and efficient approach for TARE in HCC, showing considerable promise for clinical application (ChiCTR2400087731).</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 10","pages":"Pages 5022-5035"},"PeriodicalIF":14.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229924","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":"Advances in selective targeting of serine hydrolases: A targeted covalent approach against hCES2A mitigates irinotecan toxicity in vivo","authors":"Elena De Vita","doi":"10.1016/j.apsb.2025.09.023","DOIUrl":"10.1016/j.apsb.2025.09.023","url":null,"abstract":"","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 10","pages":"Pages 5491-5492"},"PeriodicalIF":14.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229976","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}