Acta Pharmaceutica Sinica. B最新文献

{"title":"Neutrophil-mediated BDNF delivery for the treatment of moderate to severe Alzheimer’s disease","authors":"Feng Qin,&nbsp;Ni Zhang,&nbsp;Yanjiao Jiang,&nbsp;Kunyao Xu,&nbsp;Yang Xiong,&nbsp;Yuhang Liu,&nbsp;Qiuhong Ouyang,&nbsp;Haxiaoyu Liu,&nbsp;Yanping Dai,&nbsp;Linhong Jiang,&nbsp;Yue Zhao,&nbsp;Hongchun Li,&nbsp;Liang Wang,&nbsp;Yaxing Chen,&nbsp;Liqiang Hu,&nbsp;Qian Bu,&nbsp;Yinglan Zhao,&nbsp;Weihong Kuang,&nbsp;Meng Qin,&nbsp;Xiaobo Cen","doi":"10.1016/j.apsb.2026.07.009","DOIUrl":"10.1016/j.apsb.2026.07.009","url":null,"abstract":"<div><div>Alzheimer’s disease (AD), especially its moderate-to-severe stage (MSAD), remains a global health challenge with no disease-modifying therapies. Here, we identified a dual pathological signature in MSAD patients and murine models: a systemic pro-inflammatory milieu and critically reduced brain-derived neurotrophic factor (BDNF) levels in both the hippocampus and serum. To mitigate the decrease in BDNF, we developed an engineered neutrophil capsule, in which neutrophils carrying lipid nanoparticles encapsulating BDNF penetrated the brain and ameliorated cognitive capacity deficits in MSAD mice. The pro-inflammatory state in the MSAD brain facilitated neutrophil passage through the blood–brain barrier, and inflammatory mediators triggered the release of BDNF from the engineered neutrophils. Collectively, our findings show that engineered neutrophil-mediated brain delivery of BDNF efficiently reduces the amyloid-<em>β</em> plaque deposition in the hippocampus, leading to significantly improved learning and memory in MSAD mice. This study establishes neutrophil-mediated delivery as a paradigm strategy for MSAD, merging cell biology with nanotechnology to reverse neurodegeneration.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 9","pages":"Pages 6185-6202"},"PeriodicalIF":14.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148940082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tocotrienol metabolites redirect lipid mediator production in innate immune cells towards inflammation resolution","authors":"Stephan Permann,&nbsp;Elena Brunner,&nbsp;Khaled Alsabil,&nbsp;Markus Werner,&nbsp;Lorenz Waltl,&nbsp;Guillaume Viault,&nbsp;Danilo D’Avino,&nbsp;Bill Perkowski,&nbsp;Anita Siller,&nbsp;Laura Fritsch,&nbsp;Sara Perna,&nbsp;Harald Schennach,&nbsp;Denis Séraphin,&nbsp;Solveigh C. Koeberle,&nbsp;Paul M. Jordan,&nbsp;Fiorentina Roviezzo,&nbsp;Pascal Richomme,&nbsp;Antonietta Rossi,&nbsp;Jean-Jacques Helesbeux,&nbsp;Oliver Werz,&nbsp;Andreas Koeberle","doi":"10.1016/j.apsb.2026.06.056","DOIUrl":"10.1016/j.apsb.2026.06.056","url":null,"abstract":"<div><div>Restoring homeostasis in persistent inflammation requires suppressing the inflammatory response and promoting resolution. Currently, no clinically used small molecules intentionally achieve both effects. Endogenous long-chain vitamin E metabolites (LCMs) address inflammation at multiple sites, including pro-inflammatory leukotriene production and cytokine release, thus limiting inflammation. Among LCMs, we here identified <em>ω</em>-carboxylates and <em>ω</em>-alcohols that suppress leukotriene biosynthesis while enhancing the biosynthesis of prostaglandin E₂ and specialized pro-resolving mediators, specifically protectins or isomers, proposed to promote inflammation resolution. These LCMs induce a lipid mediator class switch in activated and non-activated human innate immune cells and in a mouse model of self-resolving peritonitis and inhibit ferroptosis. Changes in lipid mediator classes are tightly coordinated between local and systemic sites and follow different kinetics. Mechanistically, LCMs induce polyunsaturated fatty acid release and translocate 15-lipoxygenase-1, a key enzyme in protectin biosynthesis, to particulate locales while also engaging other mechanisms, partially involving cyclooxygenase-2, to increase protectin production. The LCMs also inhibit soluble epoxide hydrolase, reducing the degradation of anti-inflammatory epoxyeicosatrienoic acids, and increase levels of endocannabinoids and dihydroceramides with immunomodulatory and stress-protective functions. These findings provide insights into immunoregulation by tocotrienol metabolites and offer promising lead structures for redirecting lipid mediator profiles from inflammation toward resolution.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 9","pages":"Pages 6099-6128"},"PeriodicalIF":14.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148940130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elesclomol-mediated cuproptosis overcomes cisplatin resistance by restricting epigenetically activated mitochondrial respiration: Novel therapeutic insights into cisplatin–elesclomol combination therapy","authors":"Tianyu Zhu,&nbsp;Yongyun Li,&nbsp;Jieling Tang,&nbsp;Huimin Lin,&nbsp;Xiang Gu,&nbsp;Shengfang Ge,&nbsp;Lin Ye,&nbsp;Pengsen Wu,&nbsp;Xianqun Fan,&nbsp;Ai Zhuang,&nbsp;Peiwei Chai,&nbsp;Renbing Jia","doi":"10.1016/j.apsb.2026.07.027","DOIUrl":"10.1016/j.apsb.2026.07.027","url":null,"abstract":"<div><div>Chemoresistance remains a significant challenge in cancer treatment, substantially limiting therapeutic efficacy. Cuproptosis is copper-induced cell death driven by mitochondrial protein aggregation and metabolic dysfunction. However, the involvement of cuproptosis in chemoresistance remains enigmatic. This study reveals that epigenetic remodeling augments mitochondrial respiration, thereby sensitizing cells to elesclomol-induced cuproptosis in cisplatin-resistant uveal melanoma (UM). First, we established cisplatin-resistant UM cell lines, which were validated <em>in vitro</em> and <em>in vivo</em>. A multi-omics analysis, including transcriptomics, metabolomics, and histone acetylation profiling (H3K9Ac/H3K27Ac CUT&amp;Tag), revealed an upregulation of mitochondrial respiration and downregulation of glycolysis in cisplatin-resistant cells due to changes in histone acetylation. This metabolic reprogramming was associated with increased sensitivity to elesclomol-mediated cuproptosis, characterized by the diminishment of Fe–S cluster proteins and DLAT aggregation. Our research further delineated that the absence of <em>FDX1</em> not only mitigated the sensitivity of chemoresistant UM cells to elesclomol but also attenuated copper-induced cell death, thereby substantiating the pivotal role of cuproptosis in this context. Therapeutically, employing zebrafish models, orthotopic xenografts, and patient-derived xenografts (PDXs), we confirmed the therapeutic efficacy of elesclomol in overcoming chemoresistance. Collectively, our study highlights a novel avenue for the development of a combinatorial therapeutic approach employing cisplatin and elesclomol to improve chemotherapy outcomes.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 9","pages":"Pages 6030-6044"},"PeriodicalIF":14.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148940126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Red light-responsive bioorthogonal chemistry enabled on-demand prodrug activation for cancer therapy","authors":"Hanzeng Cheng,&nbsp;Yanjun Wang,&nbsp;Jiaxue Zhang,&nbsp;Zhipeng Pei,&nbsp;Qin Yan,&nbsp;Zeyu Cai,&nbsp;Dan Zhang,&nbsp;Huilong Ma,&nbsp;Hao Liu,&nbsp;Dongxue Peng,&nbsp;Zimeng Gao,&nbsp;Hongyu Yuan,&nbsp;Bing Cui,&nbsp;Xiaojing Wang,&nbsp;Rui Wang,&nbsp;Luping Liu","doi":"10.1016/j.apsb.2026.07.024","DOIUrl":"10.1016/j.apsb.2026.07.024","url":null,"abstract":"<div><div>Light-driven chemistry has revolutionized modern medicine, enabling precise disease detection and on-demand therapeutic interventions with high spatiotemporal accuracy. However, despite tremendous advances in bioorthogonal reactions, photoclick chemistry-based therapeutics remain as a challenge <em>in vivo</em>. To address this limitation, we have developed a multifunctional BODIPY-caged glucamine dihydrotetrazine (BGdTz) that integrates cancer-targeting, fluorescence imaging, and photoactivable tetrazine bioorthogonal chemistry. By targeting the overexpressed glucose transporter 1 (Glut1) on cancer cells, BGdTz specifically accumulates at the tumor site, leading to high-contrast fluorescence imaging of tumor in murine models. Subsequent irradiation of BGdTz with red light results in a spatialtemporal formation of glucamine-tetrazine. Furthermore, we have demonstrated an image-guided bioorthogonal prodrug activation between BGdTz and <em>trans</em>-cyclooctene caged doxorubicin, revealing potent antitumor efficacy and minimal systemic toxicity in A375 xenograft mouse models. In summary, we present a red light-controllable tetrazine bioorthogonal platform operable in mammals, offering a powerful tool for dual cancer diagnosis and therapy. We anticipate that this photouncaging-driven tetrazine ligation will open new avenues for precision medicine.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 9","pages":"Pages 6274-6285"},"PeriodicalIF":14.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148940583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Xiangshao granules regulate the dopaminergic synapse pathway and improve menopausal anxiety in peri- and postmenopausal Chinese women: A multi-center, double-blind, randomized controlled trial","authors":"Ruiyi Tang,&nbsp;Zhuolin Xie,&nbsp;Yubo Fan,&nbsp;Jing Zhang,&nbsp;Ling Lu,&nbsp;Yali Zhuang,&nbsp;Cunju Guo,&nbsp;Kuanyong Shu,&nbsp;Shize Li,&nbsp;Ping Zhang,&nbsp;Kun Liu,&nbsp;Yuanyuan Zhang,&nbsp;Jianghai Ji,&nbsp;Qingling Ren,&nbsp;Qingfang Meng,&nbsp;Yi Lin,&nbsp;Xianghua Huang,&nbsp;Huimin Li,&nbsp;Ying Liu,&nbsp;Qijian Deng,&nbsp;Rong Chen","doi":"10.1016/j.apsb.2026.06.024","DOIUrl":"10.1016/j.apsb.2026.06.024","url":null,"abstract":"<div><div>Anxiety is common among peri- and postmenopausal women, and many conventional treatments cause side effects. This multicenter, double-blind, randomized, placebo-controlled trial was conducted from December 2021 to June 2023 at 18 centers in China, enrolling 360 women aged 40‒65 years with menopausal anxiety. Participants were randomly assigned to receive Xiangshao granules (high-dose group, <em>n</em> = 180) or a placebo (very-low-dose group, <em>n</em> = 180) for 8 weeks. The primary outcome was the reductive ratio in self-rating anxiety scale (SAS) scores after 8 weeks, while secondary outcomes included the self-rating depression scale (SDS), Kupperman Index, and gastrointestinal symptom score (GIS). After eight weeks, the mean SAS reductive ratio was greater in the high-dose group than in the very-low-dose group (37.7% <em>vs</em>. 28.9%, <em>P</em> = 0.0052), and scores declined more in the high-dose than in the very-low-dose group, with a higher clinical improvement rate (69.8% <em>vs.</em> 56.9%, <em>P</em> = 0.0151). Although no significant between-group differences were observed for SDS, Kupperman Index, or GIS, all showed improvements from baseline. Adverse event rates were comparable. Transcriptomic analysis revealed modifications in the dopaminergic synapse pathway following Xiangshao treatment, while network pharmacology identified FOS, ATF2, and CREB1 as key dopaminergic pathway-related targets. Metabolomic data corroborated these findings. Collectively, Xiangshao granules safely and effectively alleviate menopausal anxiety, potentially by modulating dopaminergic signaling.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 9","pages":"Pages 5847-5863"},"PeriodicalIF":14.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148961104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical evaluation of GW406108X, a broad-spectrum therapeutic blocking ULK1/2-mediated autophagy to inhibit enterovirus replication","authors":"Yuhui Deborah Fong,&nbsp;Thinesshwary Yogarajah,&nbsp;Xuan Wei Khoo,&nbsp;Yi Shan Chan,&nbsp;Jasmaadiyah Binte Habib Mohameed,&nbsp;Angeline Neo,&nbsp;Bowen Yi,&nbsp;Justin Jang Hann Chu","doi":"10.1016/j.apsb.2026.06.052","DOIUrl":"10.1016/j.apsb.2026.06.052","url":null,"abstract":"<div><div><em>Enterovirus</em> D68 (EV-D68) is an emerging respiratory pathogen, with severe cases developing into acute flaccid myelitis, a paralytic condition. Despite growing concern, no approved antivirals currently exist for EV-D68, underscoring the urgent need for therapeutic discovery. Here, we report the development of a high-throughput, phenotypic-based assay to screen 7986 compounds across nine diverse compound libraries for EV-D68 antivirals, on two EV-D68-susceptible cell lines (RD and H1299). The screen identified GW406108X as a potent post-entry inhibitor of EV-D68 infection (EC₅₀: 1.804 μmol/L). Mechanistic studies using luciferase replicon assays, siRNA knockdowns, and drug-resistant mutant generation suggest that GW406108X targets the autophagy pathway through ULK1/2 inhibition. Transmission electron microscopy and fluorescence bioimaging demonstrate a significant reduction in autophagosome formation in treated, infected cells. This disruption likely impairs the virus’s ability to exploit autophagy, which may in turn hinder replication organelle formation and non-lytic virion release, leading to reduced viral replication. Preclinical evaluations showed that GW406108X demonstrates strong antiviral efficacy without detectable cytotoxicity. These findings reveal a previously uncharacterized antiviral mechanism and position GW406108X as a promising candidate for antiviral therapeutic development. Findings from this study expand the current antiviral landscape for enteroviruses and represent a significant step toward clinical intervention for EV-D68 and potentially related viral pathogens.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 9","pages":"Pages 5864-5883"},"PeriodicalIF":14.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148949553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SNX3 exacerbates hepatic fibrosis by amplifying TGF-β1/Smad signaling pathway in hepatocyte-HSC fibrotic loop","authors":"Jing Zhang,&nbsp;Yuxing Dai,&nbsp;Jiaying Yu,&nbsp;Yilin Chen,&nbsp;Dinghu Ma,&nbsp;Wenjing Yu,&nbsp;Mingxia Peng,&nbsp;Zeyu Li,&nbsp;Jing Lu,&nbsp;Honghai Xu,&nbsp;Suowen Xu,&nbsp;Duanping Sun,&nbsp;Peiqing Liu","doi":"10.1016/j.apsb.2026.06.021","DOIUrl":"10.1016/j.apsb.2026.06.021","url":null,"abstract":"<div><div>Hepatic fibrosis is a chronic disease driven by dysregulated TGF-<em>β</em>1-mediated interactions between hepatocytes and hepatic stellate cells. The molecular mechanisms controlling TGF-<em>β</em>1 degradation <em>versus</em> secretion remain poorly understood. Here, we identify sorting nexin 3 (SNX3), a retromer-associated cargo-binding protein, as a critical regulator of TGF-<em>β</em>1-driven hepatic fibrosis. SNX3 expression was significantly elevated in liver tissues from fibrosis patients and mouse models, correlating positively with TGF-<em>β</em>1 signaling. Functional studies using conditional mouse models demonstrated that hepatocyte-specific SNX3 knockout provided substantial protection against fibrosis, while overexpression induced spontaneous liver fibrosis. Mechanistically, SNX3 binds TGF-<em>β</em>1 and prevents its lysosomal degradation by promoting retention in early endosomes, thereby enhancing secretion. In hepatocytes, SNX3 increases TGF-<em>β</em>1 secretion that activates neighboring hepatic stellate cells through paracrine signaling. In activated hepatic stellate cells, elevated SNX3 expression further amplifies TGF-<em>β</em>1 production, creating a self-perpetuating fibrotic cascade leading to enhanced downstream signaling and transcriptional activation of fibrotic genes. Pharmacological studies validated therapeutic potential, with TGF-<em>β</em>1 signaling inhibition attenuating SNX3-induced fibrosis while pathway activation abolished SNX3 knockout protection, establishing SNX3 as a promising therapeutic target.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 9","pages":"Pages 6013-6029"},"PeriodicalIF":14.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148940237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances of oral micro- and nanomedicines for modulating intestinal barriers in the treatment of intestinal diseases","authors":"Mei Yang,&nbsp;Yuanyuan Zhu,&nbsp;Qian Li,&nbsp;Zhichao Deng,&nbsp;Chenxi Xu,&nbsp;Xiaodan Wei,&nbsp;Yana Ma,&nbsp;Chenguang Ding,&nbsp;Mingxin Zhang,&nbsp;Shanbo Ma,&nbsp;Mingzhen Zhang","doi":"10.1016/j.apsb.2026.06.032","DOIUrl":"10.1016/j.apsb.2026.06.032","url":null,"abstract":"<div><div>The oral delivery of drugs for treating intestinal diseases, such as inflammatory bowel disease (IBD) and colorectal cancer (CRC), is hindered by four primary intestinal barriers: chemical, microbial, mechanical, and immunological barriers. Micro- and nanoparticles have garnered significant attention as platforms for intestinal-targeted delivery due to their small size and unique structural composition, which enhance drug accumulation and prolong residence time at the site of action, thereby facilitating localized therapy. Oral micro/nanomedicines have emerged as a promising strategy to overcome these barriers and enable the selective targeting of drugs to pathological sites within the intestine. This review systematically examines the chemical, microbial, mechanical, and immune barriers of the intestinal mucosa encountered in intestinal diseases, introduces oral micro/nanomedicines designed to target these barriers, discusses their latest advancements in the context of intestinal diseases, and ultimately provides insights into the challenges faced by oral micro/nanomedicine.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 9","pages":"Pages 5730-5759"},"PeriodicalIF":14.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148940649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deconvoluting the multi-faceted roles of alternative splicing events in cancer: From underlying mechanisms to innovative therapeutics","authors":"Lei Hu,&nbsp;Xiaofang Wang,&nbsp;Bo Fan,&nbsp;Qian Zhao,&nbsp;Yajun Zhong,&nbsp;Yingying Lu,&nbsp;Minru Liao,&nbsp;Hongyao Li,&nbsp;Xiangyu Fu,&nbsp;Huiping Wang,&nbsp;Cheng Du,&nbsp;Bo Han,&nbsp;Leilei Fu","doi":"10.1016/j.apsb.2026.07.019","DOIUrl":"10.1016/j.apsb.2026.07.019","url":null,"abstract":"<div><div>Alternative splicing (AS) is well-known to be a critical mechanism to enhance proteomic diversity from a limited genome. Dysregulation of AS may represent a key tumor-specific molecular feature; thereby driving tumorigenesis and progression. Elucidating the mechanisms underlying AS dysregulation in oncogenesis is paramount for developing more novel therapeutic targets and agents. Thus, in this review, we comprehensively demonstrate the pivotal roles of AS dysregulation across the 14 established cancer hallmarks. We systematically summarize current therapeutic targets and related strategies for targeting AS in cancer, including small molecules and antisense oligonucleotides (ASOs). Moreover, we further discuss the progress, challenges, and potential solutions in drug development by providing both preclinical data and clinical trial outcomes for AS-targeted therapies. In summary, this review aims to deconvolute the multi-faceted roles of alternative splicing events in cancer from underlying mechanisms to innovative therapeutics.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 9","pages":"Pages 5622-5649"},"PeriodicalIF":14.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148961156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Engineered flavonoid disrupts mitochondrial AIF/CHCHD4 complex for targeted cancer therapy","authors":"Hong Toan Lai,&nbsp;Daniela Dias-Pedroso,&nbsp;Maria Eugénia Marques Da Costa,&nbsp;Romain Fernandes,&nbsp;Tran Ngoc Anh Nguyen,&nbsp;Olivia Bawa,&nbsp;Pierre Khneisser,&nbsp;João Gabriel Silva,&nbsp;Yassine Khalij,&nbsp;Michelangelo Campanella,&nbsp;John Griffith Jones,&nbsp;Svetlana Dokudovskaya,&nbsp;Guido Kroemer,&nbsp;Antonin Marchais,&nbsp;Nathalie Gaspar,&nbsp;Birgit Geoerger,&nbsp;Oumar Diane,&nbsp;Liuba Mazzanti,&nbsp;Tâp Ha Duong,&nbsp;Guy Lewin,&nbsp;Catherine Brenner","doi":"10.1016/j.apsb.2026.06.022","DOIUrl":"10.1016/j.apsb.2026.06.022","url":null,"abstract":"<div><div>Cancer metabolism depends on multifaceted mechanisms, including bidirectional inter-organelle communication between mitochondria and the nucleus, facilitating cellular adaptation at the transcriptomic, proteomic, and metabolomic levels. The mitochondrial protein complex composed of apoptosis-inducing factor (AIF) and coiled-coil-helix-coiled-coil-helix domain-containing protein 4 (CHCHD4) is essential for this mitochondrio-nuclear communication. The AIF/CHCHD4 complex mediates the mitochondrial import of cysteine-enriched nuclear gene-encoded proteins, thereby adapting the mitochondrial proteome to cellular energy demands. Here, we report the discovery of M30-E05, a compound that binds to the NADH pocket of AIF, preventing its dimerization and disrupting the AIF/CHCHD4 complex, as demonstrated by molecular docking and gel electrophoresis analysis of mitochondrial AIF/CHCHD4 substrate expression. In cancer cells, M30-E05 reduces the expression of nuclear gene-encoded mitochondrial proteins such as AIF, CHCHD4, cytochrome <em>c</em> oxidase copper chaperone (COX17), and Mitochondrial calcium uptake 1 (MICU1). In addition, M30-E05 fragments the mitochondrial network and impairs mitochondrial respiration, causing profound alterations, particularly in glucose, lipid, and amino acid metabolism, as revealed by kinetic measurements of oxygen consumption and mass spectrometric metabolomics. Importantly, M30-E05 significantly reduces the viability of a human adult and pediatric osteosarcoma cancer cell panel, including those from patient-derived xenografts (PDX) of osteosarcomas, and induces apoptosis. When orally administered for two weeks to immunodeficient NSG mice, M30-E05 inhibited tumor growth in a subcutaneous PDX xenograft model without apparent toxicity. We anticipate that M30-E05, as a first-in-class metabolic inhibitor, could serve as the lead compound for a new class of antineoplastic agents.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 9","pages":"Pages 6145-6167"},"PeriodicalIF":14.6,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148940133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}