Acta Pharmaceutica Sinica. B最新文献

{"title":"A novel feedback loop: CELF1/circ-CELF1/BRPF3/KAT7 in cardiac fibrosis","authors":"Yuan Jiang ,&nbsp;Bowen Zhang ,&nbsp;Bo Zhang ,&nbsp;Xinhua Song ,&nbsp;Xiangyu Wang ,&nbsp;Wei Zeng ,&nbsp;Liyang Zuo ,&nbsp;Xinqi Liu ,&nbsp;Zheng Dong ,&nbsp;Wenzheng Cheng ,&nbsp;Yang Qiao ,&nbsp;Saidi Jin ,&nbsp;Dongni Ji ,&nbsp;Xiaofei Guo ,&nbsp;Rong Zhang ,&nbsp;Xieyang Gong ,&nbsp;Lihua Sun ,&nbsp;Lina Xuan ,&nbsp;Berezhnova Tatjana Alexandrovna ,&nbsp;Xiaoxiang Guan ,&nbsp;Chaoqian Xu","doi":"10.1016/j.apsb.2025.07.036","DOIUrl":"10.1016/j.apsb.2025.07.036","url":null,"abstract":"<div><div>Cardiac fibrosis is characterized by an elevated amount of extracellular matrix (ECM) within the heart. However, the persistence of cardiac fibrosis ultimately diminishes contractility and precipitates cardiac dysfunction. Circular RNAs (circRNAs) are emerging as important regulators of cardiac fibrosis. Here, we elucidate the functional role of a specific circular RNA CELF1 in cardiac fibrosis and delineate a novel feedback loop mechanism. Functionally, circ-CELF1 was involved in enhancing fibrosis-related markers' expression and promoting the proliferation of cardiac fibroblasts (CFs), thereby exacerbating cardiac fibrosis. Mechanistically, circ-CELF1 reduced the ubiquitination-degradation rate of BRPF3, leading to an elevation of BRPF3 protein levels. Additionally, BRPF3 acted as a modular scaffold for the recruitment of histone acetyltransferase KAT7 to facilitate the induction of H3K14 acetylation within the promoters of the <em>Celf1</em> gene. Thus, the transcription of <em>Celf1</em> was dramatically activated, thereby inhibiting the subsequent response of their downstream target gene <em>Smad7</em> expression to promote cardiac fibrosis. Moreover, <em>Celf1</em> further promoted <em>Celf1</em> pre-mRNA transcription and back-splicing, thereby establishing a feedback loop for circ-CELF1 production. Consequently, a novel feedback loop involving CELF1/circ-CELF1/BRPF3/KAT7 was established, suggesting that circ-CELF1 may serve as a potential novel therapeutic target for cardiac fibrosis.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 10","pages":"Pages 5192-5211"},"PeriodicalIF":14.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229820","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":"Bacteroides fragilis-derived succinic acid promotes the degradation of uric acid by inhibiting hepatic AMPD2: Insight into how plant-based berberine ameliorates hyperuricemia","authors":"Libin Pan ,&nbsp;Ru Feng ,&nbsp;Jiachun Hu ,&nbsp;Hang Yu ,&nbsp;Qian Tong ,&nbsp;Xinyu Yang ,&nbsp;Jianye Song ,&nbsp;Hui Xu ,&nbsp;Mengliang Ye ,&nbsp;Zhengwei Zhang ,&nbsp;Jie Fu ,&nbsp;Haojian Zhang ,&nbsp;Jinyue Lu ,&nbsp;Zhao Zhai ,&nbsp;Jingyue Wang ,&nbsp;Yi Zhao ,&nbsp;Hengtong Zuo ,&nbsp;Xiang Hui ,&nbsp;Jiandong Jiang ,&nbsp;Yan Wang","doi":"10.1016/j.apsb.2025.08.009","DOIUrl":"10.1016/j.apsb.2025.08.009","url":null,"abstract":"<div><div>In recent decades, the prevalence of hyperuricemia and gout has increased dramatically due to lifestyle changes. The drugs currently recommended for hyperuricemia are associated with adverse reactions that limit their clinical use. In this study, we report that berberine (BBR) is an effective drug candidate for the treatment of hyperuricemia, with its mechanism potentially involving the modulation of gut microbiota and its metabolite, succinic acid. BBR has demonstrated good therapeutic effects in both acute and chronic animal models of hyperuricemia. In a clinical trial, oral administration of BBR for 6 months reduced blood uric acid levels in 22 participants by modulating the gut microbiota, which led to an increase in the abundance of <em>Bacteroides</em> and a decrease in <em>Clostridium sensu stricto_1</em>. Furthermore, <em>Bacteroides fragilis</em> was transplanted into ICR mice, and the results showed that <em>Bacteroides fragilis</em> exerted a therapeutic effect on uric acid similar to that of BBR. Notably, succinic acid, a metabolite of <em>Bacteroides</em>, significantly reduced uric acid levels. Subsequent cell and animal experiments revealed that the intestinal metabolite, succinic acid, regulated the upstream uric acid synthesis pathway in the liver by inhibiting adenosine monophosphate deaminase 2 (AMPD2), an enzyme responsible for converting adenosine monophosphate (AMP) to inosine monophosphate (IMP). This inhibition resulted in a decrease in IMP levels and an increase in phosphate levels. The reduction in IMP led to a decreased downstream production of hypoxanthine, xanthine, and uric acid. BBR also demonstrated excellent renoprotective effects, improving nephropathy associated with hyperuricemia. In summary, BBR has the potential to be an effective treatment for hyperuricemia through the gut–liver axis.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 10","pages":"Pages 5244-5260"},"PeriodicalIF":14.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229974","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":"Natural killer cell-derived granzyme B as a therapeutic target for alleviating graft injury during liver transplantation","authors":"Kai Wang ,&nbsp;Zhoucheng Wang ,&nbsp;Xin Shao ,&nbsp;Lijun Meng ,&nbsp;Chuanjun Liu ,&nbsp;Nasha Qiu ,&nbsp;Wenwen Ge ,&nbsp;Yutong Chen ,&nbsp;Xiao Tang ,&nbsp;Xiaodong Wang ,&nbsp;Zhengxing Lian ,&nbsp;Ruhong Zhou ,&nbsp;Shusen Zheng ,&nbsp;Xiaohui Fan ,&nbsp;Xiao Xu","doi":"10.1016/j.apsb.2025.07.042","DOIUrl":"10.1016/j.apsb.2025.07.042","url":null,"abstract":"<div><div>Liver transplantation (LT) has become a standard treatment for end-stage liver diseases, and graft injury is intricately associated with poor prognosis. Granzyme B (GZMB) plays a vital role in natural killer (NK) cell biology, but whether NK-derived GZMB affects graft injury remains elusive. Through the analysis of single-cell RNA-sequencing data obtained from human LT grafts and the isolation of lymphocytes from mouse livers following ischemia-reperfusion injury (IRI), we demonstrated that 2NK cells with high expression of GZMB are enriched in patients and mice. Both systemically and liver-targeted depletion of NK cells led to a notable reduction in GZMB⁺ cell infiltration, subsequently resulting in diminished graft injury. Notably, the reconstitution of <em>Il2rg</em>^{<em>−/−</em>}<em>Rag2</em>^{<em>−/−</em>} mice with purified <em>Gzmb</em>-KO NK cells demonstrated superior outcomes compared to those with wild-type NK cells. Crucially, global knockout of GZMB and pharmacological inhibition exhibited remarkable improvements in liver function in both mouse IRI and rat LT models. Moreover, a phosphorylated derivative of FDA-approved vidarabine was identified as an effective inhibitor of mouse GZMB activity by molecular dynamics, which could provide a potential avenue for therapeutic intervention. Therefore, targeting NK cell-derived GZMB during the LT process suggests potential therapeutic strategies to improve post-transplant outcomes.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 10","pages":"Pages 5277-5293"},"PeriodicalIF":14.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229823","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":"Succinylation of tumor suppressor PPP2R1A K541 by HAT1 converses the role in modulation of gluconeogenesis/lipogenesis remodeling to display oncogene function","authors":"Guang Yang ,&nbsp;Yufei Wang ,&nbsp;Hongfeng Yuan ,&nbsp;Huihui Zhang ,&nbsp;Lina Zhao ,&nbsp;Chunyu Hou ,&nbsp;Pan Lv ,&nbsp;Jihui Hao ,&nbsp;Xiaodong Zhang","doi":"10.1016/j.apsb.2025.07.040","DOIUrl":"10.1016/j.apsb.2025.07.040","url":null,"abstract":"<div><div>Metabolic reprogramming plays a central role in tumors. However, the key drivers modulating reprogramming of gluconeogenesis/lipogenesis are poorly understood. Here, we try to identify the mechanism by which histone acetyltransferase 1 (HAT1) confers reprogramming of gluconeogenesis/lipogenesis in liver cancer. Diethylnitrosamine (DEN)/carbon tetrachloride (CCl₄)-induced hepatocarcinogenesis was hardly observed in HAT1-knockout mice. Multi-omics identified that HAT1 modulated gluconeogenesis and lipogenesis in liver. Protein phosphatase 2 scaffold subunit alpha (PPP2R1A) promoted gluconeogenesis and inhibited lipogenesis by phosphoenolpyruvate carboxykinase 1 (PCK1) serine 90 dephosphorylation to suppress the tumor growth. HAT1 succinylated PPP2R1A at lysine 541 (K541) to block the assembly of protein phosphatase 2A (PP2A) holoenzyme and interaction with PCK1, resulting in the depression of dephosphorylation of PCK1. HAT1-succinylated PPP2R1A contributed to the remodeling of gluconeogenesis/lipogenesis by PCK1 serine 90 phosphorylation, leading to the inhibition of gluconeogenic enzyme activity and activating sterol regulatory element-binding protein 1 (SREBP1) nuclear accumulation-induced lipogenesis gene expression, which enhanced the tumor growth. In conclusion, succinylation of PPP2R1A lysine 541 by HAT1 converses the role in modulation of gluconeogenesis/lipogenesis remodeling through PCK1 S90 phosphorylation to support liver cancer. Our finding provides new insights into the mechanism by which post-translational modifications (PTMs) confer the conversion of tumor suppressor function to oncogene.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 10","pages":"Pages 5294-5311"},"PeriodicalIF":14.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229893","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":"Unraveling the meta-hallmarks between senescent and tumor cells: A new perspective for senolytic drug discovery","authors":"Wei Liu ,&nbsp;Bo Fan ,&nbsp;Te Fang ,&nbsp;Hongyao Li ,&nbsp;Jin Zhang ,&nbsp;Bo Liu ,&nbsp;Zhiyu Liu","doi":"10.1016/j.apsb.2025.08.010","DOIUrl":"10.1016/j.apsb.2025.08.010","url":null,"abstract":"<div><div>Aging and cancer share overlapping characteristics, referred to as meta-hallmarks, which elucidate the convergent, antagonistic, or contradictory relationships between aging and cancer. Likewise, as a key characteristic of aging, senescent cells share some meta-hallmarks with tumor cells. These hallmarks include apoptosis resistance, metabolic alterations, secretory phenotypes, epigenetic reprogramming, and immune surveillance, all of which play pivotal roles in both tumorigenesis and senescence. Moreover, senolytic drugs, which are a class of agents selectively designed to eliminate senescent cells, have emerged as promising therapeutic agents in oncology and aging-related diseases. Since the discovery of the first senolytic drug in 2015, a diverse array of such agents has been developed. Notably, most senolytic drugs are repurposed from existing anti-tumor therapies, leveraging their shared mechanisms with senescent cells and tumor cells. Thus, this review examines the similarities between senescent cells and tumor cells, providing a better understanding of the meta-hallmarks. Besides, we categorize existing senolytic drugs based upon meta-hallmarks and elucidate the potential molecular mechanisms underlying their effects. By integrating insights from cancer and senescence research, this work aims to inspire innovative strategies for senolytic drug discovery.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 10","pages":"Pages 5071-5098"},"PeriodicalIF":14.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229927","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":"New insights into translational research in Alzheimer's disease guided by artificial intelligence, computational and systems biology","authors":"Shulan Jiang ,&nbsp;Zixi Tian ,&nbsp;Yuchen Yang ,&nbsp;Xiang Li ,&nbsp;Feiyan Zhou ,&nbsp;Jianhua Cheng ,&nbsp;Jihui Lyu ,&nbsp;Tingting Gao ,&nbsp;Ping Zhang ,&nbsp;Hongbin Han ,&nbsp;Zhiqian Tong","doi":"10.1016/j.apsb.2025.08.015","DOIUrl":"10.1016/j.apsb.2025.08.015","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is characterized by cognitive and functional deterioration, with pathological features such as amyloid-beta (A<em>β</em>) aggregates in the extracellular spaces of parenchymal neurons and intracellular neurofibrillary tangles formed by the hyperphosphorylation of tau protein. Despite a thorough investigation, current treatments targeting the reduction of A<em>β</em> production, promotion of its clearance, and inhibition of tau protein phosphorylation and aggregation have not met clinical expectations, posing a substantial obstacle in the development of drugs for AD. Recently, artificial intelligence (AI), computational biology (CB), and systems biology (SB) have emerged as promising methodologies in AD research. Their capacity to analyze extensive and varied datasets facilitates the identification of intricate patterns, thereby enriching our comprehension of AD pathology. This paper provides a comprehensive examination of the utilization of AI, CB, and SB in the diagnosis of AD, including the use of imaging omics for early detection, drug discovery methods such as lecanemab, and complementary therapies like phototherapy. This review offers novel perspectives and potential avenues for further research in the realm of translational AD studies.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 10","pages":"Pages 5099-5126"},"PeriodicalIF":14.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229928","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":"VIRMA-mediated SHQ1 m6A modification enhances liver regeneration through an HNRNPA2B1-dependent mechanism","authors":"Hao Chen ,&nbsp;Haichuan Wang ,&nbsp;Jiwei Huang ,&nbsp;Guoteng Qiu ,&nbsp;Zheng Zhang ,&nbsp;Lin Xu ,&nbsp;Xiao Ma ,&nbsp;Zhen Wang ,&nbsp;Xiangzheng Chen ,&nbsp;Yong Zeng","doi":"10.1016/j.apsb.2025.07.025","DOIUrl":"10.1016/j.apsb.2025.07.025","url":null,"abstract":"<div><div><em>N</em>6-Methyladenosine (m6A) modification is a crucial post-transcriptional regulatory mechanism and the most abundant and highly conserved RNA epigenetic modification in eukaryotes. Previous studies have indicated the involvement of m6A modification in various tissue regeneration processes, including liver regeneration. Vir-like m6A methyltransferase associated protein (VIRMA) is an m6A methyltransferase with robust methylation capability. However, its role in liver regeneration remains poorly understood. In this study, we generated liver-specific <em>Virma</em> knockout mice using the Cre-loxP system and investigated the biological functions of VIRMA in liver regeneration using both the Associating Liver Partition and Portal vein Ligation for Staged Hepatectomy (ALPPS) mouse model and the carbon tetrachloride (CCl₄) mouse model. The expression level of VIRMA was rapidly up-regulated after ALPPS surgery and gradually down-regulated during liver repair. <em>Virma</em> deficiency significantly impaired liver regeneration capacity and disrupted cell cycle progression. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) analysis revealed that <em>Shq1</em> is an effective downstream target of VIRMA-mediated m6A modification. The upregulation of <em>Shq1</em> enhanced the proliferation ability of cells, which was attenuated by the specific AKT inhibitor ipatasertib. Supplementation of <em>Shq1 in vivo</em> alleviated the liver cell proliferation inhibition caused by <em>Virma</em> deficiency. Furthermore, the m6A-binding protein heterogeneous nuclear ribonucleoprotein a2b1 (HNRNPA2B1) enhanced the mRNA stability of <em>Shq1</em>. Mechanistically, <em>Virma</em> deficiency resulted in decreased m6A modification on <em>Shq1</em> mRNA, leading to reduced binding ability of m6A-binding protein HNRNPA2B1 with <em>Shq1</em>, thereby decreasing the mRNA stability of <em>Shq1</em> and reducing its protein expression level. Downregulation of <em>Shq1</em> inhibited the PI3K/AKT pathway, thereby suppressing cell proliferation and cell cycle progression, ultimately impeding liver regeneration. In summary, our results demonstrate that VIRMA plays a critical role in promoting liver regeneration by regulating m6A modification, providing valuable insights into the epigenetic regulation during liver regeneration.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 10","pages":"Pages 5212-5230"},"PeriodicalIF":14.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229970","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":"Self-illuminating liposome-derived in situ triggerable photodynamic therapy combining radionuclide therapy for synergistic treatment of lung cancer","authors":"Chunsen Yuan ,&nbsp;Taotao Jin ,&nbsp;Hangke Lei ,&nbsp;Juanjuan Liu ,&nbsp;Wendan Pu ,&nbsp;Yang Zhang ,&nbsp;Chenwen Li ,&nbsp;Dingde Huang ,&nbsp;Jianxiang Zhang ,&nbsp;Jiawei Guo","doi":"10.1016/j.apsb.2025.06.026","DOIUrl":"10.1016/j.apsb.2025.06.026","url":null,"abstract":"<div><div>The persistent high prevalence and poor survival outcomes of lung cancer underscore the urgent need for innovative therapeutic modalities. Here, we present a novel multifunctional delivery platform for the synergistic treatment of lung malignancies, combining <em>in situ</em>-triggerable photodynamic therapy (PDT) with radiotherapy. The new platform CLL was developed by loading a new reactive oxygen species (ROS)-triggerable photosensitizer, luminol-conjugated chlorin e6 (Ce6), into liposomes. CLL can be activated through the bioluminescence resonance energy transfer effect under oxidative stress, thereby producing singlet oxygen for targeted tumor treatment without external irradiation. <em>In vitro</em> studies showed significant cytotoxic effects of CLL in both 4T1 and A549 tumor cells. Furthermore, a PDT-radiopharmaceutical combination nanotherapy CLL-¹⁷⁷Lu was engineered by incorporating the radionuclide ¹⁷⁷Lu into CLL. CLL-¹⁷⁷Lu demonstrated synergistic antitumor effects in 4T1 and A549 tumor cells, as well as in mouse models of 4T1 breast cancer lung metastasis or A549 tumor xenografts. Mechanistically, CLL-¹⁷⁷Lu can induce singlet oxygen/ROS generation, enhance tumor cell apoptosis, and promote M1 macrophage-mediated immunotherapy. Preliminary assessments showed a favorable profile for CLL-¹⁷⁷Lu, highlighting its potential as a promising nanotherapy for cancer treatment. Additionally, CLL can serve as a versatile platform for delivering a range of therapies to achieve synergistic antitumor effects.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 10","pages":"Pages 4973-4994"},"PeriodicalIF":14.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229979","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 mechanism underlying the association of Aβ plaque and lipid droplets in Alzheimer's disease","authors":"Lixuan Ren ,&nbsp;Xiwen Ma ,&nbsp;Jianping Ye","doi":"10.1016/j.apsb.2025.06.018","DOIUrl":"10.1016/j.apsb.2025.06.018","url":null,"abstract":"","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 10","pages":"Pages 5486-5488"},"PeriodicalIF":14.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229817","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":"Evolution-guided design of mini-protein for high-contrast in vivo imaging","authors":"Nongyu Huang ,&nbsp;Yang Cao ,&nbsp;Guangjun Xiong ,&nbsp;Suwen Chen ,&nbsp;Juan Cheng ,&nbsp;Yifan Zhou ,&nbsp;Chengxin Zhang ,&nbsp;Xiaoqiong Wei ,&nbsp;Wenling Wu ,&nbsp;Yawen Hu ,&nbsp;Pei Zhou ,&nbsp;Guolin Li ,&nbsp;Fulei Zhao ,&nbsp;Fanlian Zeng ,&nbsp;Xiaoyan Wang ,&nbsp;Jiadong Yu ,&nbsp;Chengcheng Yue ,&nbsp;Xinai Cui ,&nbsp;Kaijun Cui ,&nbsp;Huawei Cai ,&nbsp;Jiong Li","doi":"10.1016/j.apsb.2025.07.015","DOIUrl":"10.1016/j.apsb.2025.07.015","url":null,"abstract":"<div><div>Traditional development of small protein scaffolds has relied on display technologies and mutation-based engineering, which limit sequence and functional diversity, thereby constraining their therapeutic and application potential. Protein design tools have significantly advanced the creation of novel protein sequences, structures, and functions. However, further improvements in design strategies are still needed to more efficiently optimize the functional performance of protein-based drugs and enhance their druggability. Here, we extended an evolution-based design protocol to create a novel minibinder, BindHer, against the human epidermal growth factor receptor 2 (HER2). It not only exhibits super stability and binding selectivity but also demonstrates remarkable properties in tissue specificity. Radiolabeling experiments with ^99mTc, ⁶⁸Ga, and ¹⁸F revealed that BindHer efficiently targets tumors in HER2-positive breast cancer mouse models, with minimal nonspecific liver absorption, outperforming scaffolds designed through traditional engineering. These findings highlight a new rational approach to automated protein design, offering significant potential for large-scale applications in therapeutic mini-protein development.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 10","pages":"Pages 5327-5345"},"PeriodicalIF":14.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145229822","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}