Pub Date : 2026-01-01DOI: 10.1016/j.apsb.2025.10.027
Qiyuan An , Riqing Wei , Zhicheng Huang , Youyong Tang , Minghao Wang , Sixiao He , Kaihua Huang , Zhifeng Liu , Meimei Zhang , Ru Li , Junhao Huang , Keying Zhang , Jingjing Ji , Liwei Xie , Qiang Ma
Heat stroke (HS) is a severe medical emergency characterized by coagulation and high mortality due to organ injury. This study identifies a novel mechanism in which platelet ferroptosis, driven by transferrin receptor 1 (Tfr1) palmitoylation, significantly contributes to liver injury in HS. Our findings reveal a strong inverse correlation between platelet count and organ damage, especially liver injury, as well as mortality rates. Using murine models, we demonstrate that inhibiting Tfr1-mediated ferroptosis in platelets mitigates thrombocytopenia and decreases Interleukin-1β (IL-1β) secretion, thereby improving liver function and survival outcomes. This research highlights Tfr1 palmitoylation as a critical factor in iron transport within platelets, with the palmitoylation inhibitor 2-bromopalmitate (2BP) effectively reducing total iron, Fe2+, lipid ROS, 4-hydroxynonenal (4-HNE), and cell cytotoxicity under heat stress. These results suggest that targeting Tfr1 palmitoylation-dependent ferroptosis in platelets offers a novel therapeutic strategy for treating HS-induced thrombocytopenia and liver injury.
{"title":"Palmitoylation of Tfr1 enhances platelet ferroptosis and liver injury in heat stroke","authors":"Qiyuan An , Riqing Wei , Zhicheng Huang , Youyong Tang , Minghao Wang , Sixiao He , Kaihua Huang , Zhifeng Liu , Meimei Zhang , Ru Li , Junhao Huang , Keying Zhang , Jingjing Ji , Liwei Xie , Qiang Ma","doi":"10.1016/j.apsb.2025.10.027","DOIUrl":"10.1016/j.apsb.2025.10.027","url":null,"abstract":"<div><div>Heat stroke (HS) is a severe medical emergency characterized by coagulation and high mortality due to organ injury. This study identifies a novel mechanism in which platelet ferroptosis, driven by transferrin receptor 1 (Tfr1) palmitoylation, significantly contributes to liver injury in HS. Our findings reveal a strong inverse correlation between platelet count and organ damage, especially liver injury, as well as mortality rates. Using murine models, we demonstrate that inhibiting Tfr1-mediated ferroptosis in platelets mitigates thrombocytopenia and decreases Interleukin-1<em>β</em> (IL-1<em>β</em>) secretion, thereby improving liver function and survival outcomes. This research highlights Tfr1 palmitoylation as a critical factor in iron transport within platelets, with the palmitoylation inhibitor 2-bromopalmitate (2BP) effectively reducing total iron, Fe<sup>2+</sup>, lipid ROS, 4-hydroxynonenal (4-HNE), and cell cytotoxicity under heat stress. These results suggest that targeting Tfr1 palmitoylation-dependent ferroptosis in platelets offers a novel therapeutic strategy for treating HS-induced thrombocytopenia and liver injury.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 1","pages":"Pages 270-286"},"PeriodicalIF":14.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941392","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}
Pub Date : 2026-01-01DOI: 10.1016/j.apsb.2025.11.031
Xuquan Xian , Ruyi Gong , Shunzi Rong , Zhihao Zhang , Fengtong Jia , Lin Li , Zhengguo Chen , Beatrice Eymin , Tao Jia
Fibroblast growth factor receptor (FGFR) signaling is a pivotal regulator of tumor progression, driving cell proliferation, survival, metastasis, and therapeutic resistance across diverse cancer types. RNA alternative splicing profoundly shapes FGFR isoform diversity, endowing tumors with heterogeneity and adaptability to targeted interventions. While significant progress has been made in identifying splicing regulators that govern FGFR pre-mRNA processing, the extracellular cues influencing this process and the reciprocal impact of FGFR signaling pathway on global splicing networks remain underexplored. This review provides a comprehensive overview of the bidirectional interplay linking FGFR signaling and RNA splicing in cancer. Mechanistically, we first detail how FGFR mutations, epigenetic modifications, and crosstalks with oncogenic pathways reprogram splicing to generate tumor-specific FGFR splice variants. We then systematically classify distinct FGFR isoforms and delineate how they contribute to main cancer hallmarks, underscoring the central role of the FGFR–splicing axis in driving tumor plasticity, heterogeneity and adaptive progression. Conversely, we also examine how FGFR signaling modulates RNA splicing programs beyond FGFR itself, reshaping global splicing events that contribute to tumorigenesis, an emerging and still largely unexplored area of cancer biology. From therapeutic perspective, we highlight emerging strategies targeting the axis. Notably, FGFR splicing isoform-directed radiopharmaceuticals hold great promise for patient stratification and biomarker-directed theranostics, providing a precise approach to identify aggressive tumors and guide tailored interventions. As well, complementary approaches, including CRISPR/Cas9-based splicing modulation and long non-coding RNAs-targeted therapies, further expand the toolbox for isoform-specific intervention. Moreover, integrating splicing modulators with FGFR TKIs may overcome drug resistance. Understanding the intricate interplay between FGFR signaling and RNA splicing will not only advance biomarker-guided therapeutic development but also provide a novel framework to counteract tumor adaptability, ultimately improving outcomes in FGFR-driven malignancies.
{"title":"Unraveling the FGFR–RNA splicing axis: Mechanisms, oncogenic crosstalks and innovations for therapeutic purpose","authors":"Xuquan Xian , Ruyi Gong , Shunzi Rong , Zhihao Zhang , Fengtong Jia , Lin Li , Zhengguo Chen , Beatrice Eymin , Tao Jia","doi":"10.1016/j.apsb.2025.11.031","DOIUrl":"10.1016/j.apsb.2025.11.031","url":null,"abstract":"<div><div>Fibroblast growth factor receptor (FGFR) signaling is a pivotal regulator of tumor progression, driving cell proliferation, survival, metastasis, and therapeutic resistance across diverse cancer types. RNA alternative splicing profoundly shapes FGFR isoform diversity, endowing tumors with heterogeneity and adaptability to targeted interventions. While significant progress has been made in identifying splicing regulators that govern FGFR pre-mRNA processing, the extracellular cues influencing this process and the reciprocal impact of FGFR signaling pathway on global splicing networks remain underexplored. This review provides a comprehensive overview of the bidirectional interplay linking FGFR signaling and RNA splicing in cancer. Mechanistically, we first detail how <em>FGFR</em> mutations, epigenetic modifications, and crosstalks with oncogenic pathways reprogram splicing to generate tumor-specific FGFR splice variants. We then systematically classify distinct FGFR isoforms and delineate how they contribute to main cancer hallmarks, underscoring the central role of the FGFR–splicing axis in driving tumor plasticity, heterogeneity and adaptive progression. Conversely, we also examine how FGFR signaling modulates RNA splicing programs beyond FGFR itself, reshaping global splicing events that contribute to tumorigenesis, an emerging and still largely unexplored area of cancer biology. From therapeutic perspective, we highlight emerging strategies targeting the axis. Notably, FGFR splicing isoform-directed radiopharmaceuticals hold great promise for patient stratification and biomarker-directed theranostics, providing a precise approach to identify aggressive tumors and guide tailored interventions. As well, complementary approaches, including CRISPR/Cas9-based splicing modulation and long non-coding RNAs-targeted therapies, further expand the toolbox for isoform-specific intervention. Moreover, integrating splicing modulators with FGFR TKIs may overcome drug resistance. Understanding the intricate interplay between FGFR signaling and RNA splicing will not only advance biomarker-guided therapeutic development but also provide a novel framework to counteract tumor adaptability, ultimately improving outcomes in FGFR-driven malignancies.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 1","pages":"Pages 35-61"},"PeriodicalIF":14.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941475","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}
Pub Date : 2026-01-01DOI: 10.1016/j.apsb.2025.10.006
Xiaoxuan Hong , Xianfu Li , Xiaolu Han , Jinghu Lou , Yue Li , Jintao Lin , Yi Cheng , Haonan Xing , Hui Zhang , Xiwei Wang , Shuang Zhang , Nan Liu , Zengming Wang , Chunying Cui , Aiping Zheng
During the COVID-19 pandemic, the use of lipid nanoparticles (LNPs) augmented the development of mRNA vaccines. However, their ultralow-temperature storage and transportation requirements, as well as their heavy reliance on injection by professional medical staff, have limited large-scale vaccination in many developing countries. Herein, we developed a simple and widely deployable microneedle (MN) vaccine delivery system (mLNP-man-MN) for mannose-modified LNPs (mLNP-man) loaded with mRNA encoding the SARS-CoV-2 spike receptor-binding domain by utilizing three-dimensional printing and polydimethylsiloxane micro molding methods. This delivery system is composed of a dissolvable polymer mixture that was optimized for high bioactivity by screening formulations in vitro. We have demonstrated that this MN system can maintain the physicochemical properties and bioactivity of the mRNA-LNP complex even when stored at 4 °C for at least one month or at 25 °C for two weeks. Moreover, mLNP-man-MNs target the epidermis and dermis, which are rich in antigen-presenting cells, thereby eliciting effective innate immune responses and inducing robust systemic humoral responses, as well as multifunctional cellular immunity in the spleen. Importantly, the MN system induced a certain level of pulmonary T-cell responses compared to those induced by intramuscular injections, thereby providing some protection against lung invasion by the SARS-CoV-2 pseudovirus in mice.
{"title":"An innovative and stable mRNA-LNP microneedle vaccine elicits humoral and multifunctional cellular immune responses","authors":"Xiaoxuan Hong , Xianfu Li , Xiaolu Han , Jinghu Lou , Yue Li , Jintao Lin , Yi Cheng , Haonan Xing , Hui Zhang , Xiwei Wang , Shuang Zhang , Nan Liu , Zengming Wang , Chunying Cui , Aiping Zheng","doi":"10.1016/j.apsb.2025.10.006","DOIUrl":"10.1016/j.apsb.2025.10.006","url":null,"abstract":"<div><div>During the COVID-19 pandemic, the use of lipid nanoparticles (LNPs) augmented the development of mRNA vaccines. However, their ultralow-temperature storage and transportation requirements, as well as their heavy reliance on injection by professional medical staff, have limited large-scale vaccination in many developing countries. Herein, we developed a simple and widely deployable microneedle (MN) vaccine delivery system (mLNP-man-MN) for mannose-modified LNPs (mLNP-man) loaded with mRNA encoding the SARS-CoV-2 spike receptor-binding domain by utilizing three-dimensional printing and polydimethylsiloxane micro molding methods. This delivery system is composed of a dissolvable polymer mixture that was optimized for high bioactivity by screening formulations <em>in vitro</em>. We have demonstrated that this MN system can maintain the physicochemical properties and bioactivity of the mRNA-LNP complex even when stored at 4 °C for at least one month or at 25 °C for two weeks. Moreover, mLNP-man-MNs target the epidermis and dermis, which are rich in antigen-presenting cells, thereby eliciting effective innate immune responses and inducing robust systemic humoral responses, as well as multifunctional cellular immunity in the spleen. Importantly, the MN system induced a certain level of pulmonary T-cell responses compared to those induced by intramuscular injections, thereby providing some protection against lung invasion by the SARS-CoV-2 pseudovirus in mice.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 1","pages":"Pages 503-521"},"PeriodicalIF":14.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941497","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}
Pub Date : 2026-01-01DOI: 10.1016/j.apsb.2025.10.028
Tong Che , Yixiang Chen , Xinyu Cheng , Han Hu , Xiaoyun Wu , Yuting Zhang , Xiaoqiang Yang , Yinzhen Liu , Hui Liu , Weiwei Nan , Shuangyan Wan , Mingxing Yang , Bo Zeng , Jian Li , Jin Zhang , Bing Xiong
Recent advances in ion channel structural biology have enhanced structure-based drug design, yet lipid-occupied binding pockets—often large and flat—remain a major hurdle for developing selective small molecules. TRPC5, a brain-enriched channel regulating depression and anxiety, is a promising therapeutic target, but current preclinical candidates suffer from moderate off-target effects. To address this, we designed macrocyclic TRPC5 inhibitors using structure-guided macrocyclization, overcoming lipid-binding site challenges. Among these, JDIC-127 exhibited unprecedented potency with IC50 of 374 pmol/L—200-fold more potent than HC-070—and exceptional selectivity. Its specificity arises from interactions with unique structural features near the S5 and S6 helices of TRPC5, minimizing activity against related TRPC channels and other ion channels. This selective inhibition aligns with preclinical evidence supporting JDIC-127's potential in treating neuropsychiatric disorders. The study demonstrates how macrocycles stabilize ligand conformations, enhance affinity, and achieve selectivity in lipid-dominated binding sites. It also highlights the synergy between macrocyclic design, cryo-EM, and computational modeling to address longstanding obstacles in ion channel drug discovery. JDIC-127 serves as a proof-of-concept for the application of macrocyclization in ion channel pharmacology, offering a roadmap for developing innovative therapeutics targeting TRP channels and beyond, with implications for a wide range of diseases.
{"title":"Structure-guided design of picomolar-level macrocyclic TRPC5 channel inhibitors with antidepressant activity","authors":"Tong Che , Yixiang Chen , Xinyu Cheng , Han Hu , Xiaoyun Wu , Yuting Zhang , Xiaoqiang Yang , Yinzhen Liu , Hui Liu , Weiwei Nan , Shuangyan Wan , Mingxing Yang , Bo Zeng , Jian Li , Jin Zhang , Bing Xiong","doi":"10.1016/j.apsb.2025.10.028","DOIUrl":"10.1016/j.apsb.2025.10.028","url":null,"abstract":"<div><div>Recent advances in ion channel structural biology have enhanced structure-based drug design, yet lipid-occupied binding pockets—often large and flat—remain a major hurdle for developing selective small molecules. TRPC5, a brain-enriched channel regulating depression and anxiety, is a promising therapeutic target, but current preclinical candidates suffer from moderate off-target effects. To address this, we designed macrocyclic TRPC5 inhibitors using structure-guided macrocyclization, overcoming lipid-binding site challenges. Among these, JDIC-127 exhibited unprecedented potency with IC<sub>50</sub> of 374 pmol/L—200-fold more potent than HC-070—and exceptional selectivity. Its specificity arises from interactions with unique structural features near the S5 and S6 helices of TRPC5, minimizing activity against related TRPC channels and other ion channels. This selective inhibition aligns with preclinical evidence supporting JDIC-127's potential in treating neuropsychiatric disorders. The study demonstrates how macrocycles stabilize ligand conformations, enhance affinity, and achieve selectivity in lipid-dominated binding sites. It also highlights the synergy between macrocyclic design, cryo-EM, and computational modeling to address longstanding obstacles in ion channel drug discovery. JDIC-127 serves as a proof-of-concept for the application of macrocyclization in ion channel pharmacology, offering a roadmap for developing innovative therapeutics targeting TRP channels and beyond, with implications for a wide range of diseases.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 1","pages":"Pages 371-386"},"PeriodicalIF":14.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941529","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}
Pub Date : 2026-01-01DOI: 10.1016/j.apsb.2025.10.022
Deby Fajar Mardhian , Kunal P. Pednekar , Ahmed G. Hemdan , Praneeth Reddy Kuninty , Saadia A. Karim , Sabine de Winter , Josbert M. Metselaar , Jennifer P. Morton , Jai Prakash
The tumor–stroma interaction contributes to the aggressive and resistance nature of pancreatic ductal adenocarcinoma (PDAC), leading to treatment failure. Cancer-associated fibroblasts (CAFs), a key cell type in the stroma, produce abundant extracellular matrix (ECM) and exhibit crosstalk with cancer cells inducing chemoresistance. In this study, we designed a cyclic peptide (cyAV3.3) targeting integrin α5 (ITGA5) to disrupt CAF-induced desmoplasia and crosstalk with cancer cells. In vitro, cyAV3.3 inhibited the differentiation of pancreatic stellate cells into CAFs and reduced ECM production. In 3D co-cultured human spheroid models, the peptide decreased markers of resistance (ABCG1, BCL2, CXCR4), stemness (WNT1, CD44) and ECM remodeling (COL1A1, MMP2/9, LOX) and enhanced gemcitabine efficacy. In vivo, radiolabeled cyAV3.3 exhibited high tumor accumulation and retention following parenteral injections in a co-injection xenograft tumor model. Intriguingly, combination of cyAV3.3 with gemcitabine resulted in improved therapeutic efficacy of gemcitabine in co-injection xenograft and genetically engineered LSL-KrasG12D/+LSL-Trp53R172H/+Pdx1-Cre (KPC) PDAC models. These effects were attributed to reduced desmoplasia, vasculature compression and enhanced infiltration of cytotoxic T cells and apoptosis. This study presents a novel cyclic peptide inhibiting ITGA5-mediated tumor–stroma interaction and thereby reduce desmoplasia and resistance, ultimately enhancing chemotherapy efficacy in PDAC.
{"title":"Engineered cyclic peptide targeting ITGA5 disrupts tumor–stroma interaction to overcome desmoplasia and resistance in pancreatic ductal adenocarcinoma","authors":"Deby Fajar Mardhian , Kunal P. Pednekar , Ahmed G. Hemdan , Praneeth Reddy Kuninty , Saadia A. Karim , Sabine de Winter , Josbert M. Metselaar , Jennifer P. Morton , Jai Prakash","doi":"10.1016/j.apsb.2025.10.022","DOIUrl":"10.1016/j.apsb.2025.10.022","url":null,"abstract":"<div><div>The tumor–stroma interaction contributes to the aggressive and resistance nature of pancreatic ductal adenocarcinoma (PDAC), leading to treatment failure. Cancer-associated fibroblasts (CAFs), a key cell type in the stroma, produce abundant extracellular matrix (ECM) and exhibit crosstalk with cancer cells inducing chemoresistance. In this study, we designed a cyclic peptide (cyAV3.3) targeting integrin <em>α</em>5 (ITGA5) to disrupt CAF-induced desmoplasia and crosstalk with cancer cells. <em>In vitro</em>, cyAV3.3 inhibited the differentiation of pancreatic stellate cells into CAFs and reduced ECM production. In 3D co-cultured human spheroid models, the peptide decreased markers of resistance (ABCG1, BCL2, CXCR4), stemness (WNT1, CD44) and ECM remodeling (COL1A1, MMP2/9, LOX) and enhanced gemcitabine efficacy. <em>In vivo</em>, radiolabeled cyAV3.3 exhibited high tumor accumulation and retention following parenteral injections in a co-injection xenograft tumor model. Intriguingly, combination of cyAV3.3 with gemcitabine resulted in improved therapeutic efficacy of gemcitabine in co-injection xenograft and genetically engineered <em>LSL-Kras</em><sup>G12D/+</sup> <em>LSL-Trp53</em><sup>R172H/+</sup> <em>Pdx1-Cre</em> (KPC) PDAC models. These effects were attributed to reduced desmoplasia, vasculature compression and enhanced infiltration of cytotoxic T cells and apoptosis. This study presents a novel cyclic peptide inhibiting ITGA5-mediated tumor–stroma interaction and thereby reduce desmoplasia and resistance, ultimately enhancing chemotherapy efficacy in PDAC.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 1","pages":"Pages 305-321"},"PeriodicalIF":14.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941467","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}
Pub Date : 2026-01-01DOI: 10.1016/j.apsb.2025.11.015
Tao Yuan , Weihua Wang , Ruilin Wu , Yue Liu , Junwei Fu , Jiamin Du , Meijia Qian , Jia’er Wang , Yubo Zhang , Wencheng Kong , Ronggui Hu , Tianhua Zhou , Qiaojun He , Bo Yang , Hong Zhu
Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation is associated with the poor prognosis of colorectal cancer (CRC) patients, but the therapeutic strategies targeting KRAS are limited, and novel intervention strategies are urgently needed. The dysfunction of deubiquitinases (DUBs) is widely involved in the progression of malignancy, and DUBs are considered ideal anti-tumor targets due to their well-defined structures and catalytic sites. In our study, through DUB inhibitors screening and liquid chromatography-tandem mass spectrometry (LC–MS/MS) analysis, we identified that ubiquitin-specific protease 10 (USP10) functions as a potent DUB regulating KRAS mutants' activity. Mechanistically, USP10 directly binds to and promotes KRAS variants' activity across different mutants by removing the latter’s non-proteolytic ubiquitination chains mainly containing K6, K11, K27 and K29-linkage; while the activated KRAS mutants reciprocally upregulate USP10 levels by phosphorylating the latter at Thr42/Ser337, therefore forming a positive feedback circuit and synergistically promoting KRAS-mutant CRC growth. Moreover, we found that USP10 is elevated in KRAS-mutant CRC tissues and depletion of USP10 preferentially impeded KRAS-mutant CRC growth in vitro/in vivo. Our findings not only uncover the critical roles of the USP10/KRAS positive feedback circuit in promoting KRAS-mutant CRC growth, but also offer novel therapeutic strategies for CRC patients harboring KRAS variants across different mutants by targeting USP10.
{"title":"USP10-mediated deubiquitination and activation of KRAS mutants promotes colorectal cancer via a novel USP10/KRAS positive feedback circuit","authors":"Tao Yuan , Weihua Wang , Ruilin Wu , Yue Liu , Junwei Fu , Jiamin Du , Meijia Qian , Jia’er Wang , Yubo Zhang , Wencheng Kong , Ronggui Hu , Tianhua Zhou , Qiaojun He , Bo Yang , Hong Zhu","doi":"10.1016/j.apsb.2025.11.015","DOIUrl":"10.1016/j.apsb.2025.11.015","url":null,"abstract":"<div><div>Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation is associated with the poor prognosis of colorectal cancer (CRC) patients, but the therapeutic strategies targeting KRAS are limited, and novel intervention strategies are urgently needed. The dysfunction of deubiquitinases (DUBs) is widely involved in the progression of malignancy, and DUBs are considered ideal anti-tumor targets due to their well-defined structures and catalytic sites. In our study, through DUB inhibitors screening and liquid chromatography-tandem mass spectrometry (LC–MS/MS) analysis, we identified that ubiquitin-specific protease 10 (USP10) functions as a potent DUB regulating <em>KRAS</em> mutants' activity. Mechanistically, USP10 directly binds to and promotes <em>KRAS</em> variants' activity across different mutants by removing the latter’s non-proteolytic ubiquitination chains mainly containing K6, K11, K27 and K29-linkage; while the activated <em>KRAS</em> mutants reciprocally upregulate USP10 levels by phosphorylating the latter at Thr42/Ser337, therefore forming a positive feedback circuit and synergistically promoting <em>KRAS</em>-mutant CRC growth. Moreover, we found that USP10 is elevated in <em>KRAS</em>-mutant CRC tissues and depletion of USP10 preferentially impeded <em>KRAS</em>-mutant CRC growth <em>in vitro</em>/<em>in vivo</em>. Our findings not only uncover the critical roles of the USP10/KRAS positive feedback circuit in promoting <em>KRAS</em>-mutant CRC growth, but also offer novel therapeutic strategies for CRC patients harboring KRAS variants across different mutants by targeting USP10.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 1","pages":"Pages 322-336"},"PeriodicalIF":14.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941468","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}
Traditional drug discovery suffers from low efficiency and high attrition rates, largely due to the complexity and heterogeneity of human diseases. Omics technologies offer a systems-level perspective for uncovering disease mechanisms and identifying therapeutic targets, but present challenges such as high dimensionality, noise, and heterogeneity. Large language models (LLMs), originally developed for natural language processing, are emerging as powerful tools to address these issues by capturing complex patterns and inferring missing information from large, noisy datasets. We present a three-part framework: (1) Analyzing how LLM architectures and learning paradigms handle challenges specific to genomics, transcriptomics, and proteomics data; (2) Detailing LLM applications in key areas: uncovering disease mechanisms, identifying drug targets, predicting drug response, and simulating cellular behavior; (3) Discussing how insights from omics-integrated LLMs can inform the development of drugs targeting specific pathways, moving beyond single targets towards strategies grounded in underlying disease biology. This framework provides both conceptual insights and practical guidance for leveraging LLMs in omics-driven drug discovery and development.
{"title":"Omics-based large language models: A new engine for drug discovery innovation","authors":"Xia Sheng , Xiaoya Zhang , Yuxin Xing , Yuqi Shi , Chuanlong Zeng , Xiaochu Tong , Mingyue Zheng , Xutong Li","doi":"10.1016/j.apsb.2025.10.034","DOIUrl":"10.1016/j.apsb.2025.10.034","url":null,"abstract":"<div><div>Traditional drug discovery suffers from low efficiency and high attrition rates, largely due to the complexity and heterogeneity of human diseases. Omics technologies offer a systems-level perspective for uncovering disease mechanisms and identifying therapeutic targets, but present challenges such as high dimensionality, noise, and heterogeneity. Large language models (LLMs), originally developed for natural language processing, are emerging as powerful tools to address these issues by capturing complex patterns and inferring missing information from large, noisy datasets. We present a three-part framework: (1) Analyzing how LLM architectures and learning paradigms handle challenges specific to genomics, transcriptomics, and proteomics data; (2) Detailing LLM applications in key areas: uncovering disease mechanisms, identifying drug targets, predicting drug response, and simulating cellular behavior; (3) Discussing how insights from omics-integrated LLMs can inform the development of drugs targeting specific pathways, moving beyond single targets towards strategies grounded in underlying disease biology. This framework provides both conceptual insights and practical guidance for leveraging LLMs in omics-driven drug discovery and development.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 1","pages":"Pages 122-136"},"PeriodicalIF":14.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941478","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}
Pub Date : 2026-01-01DOI: 10.1016/j.apsb.2025.10.031
Yu Zhu , Zhibi Zhang , Xueqin Dai , Wenjing Liu , Jian Sun , Jialing Liu , Yuxin Zhao , Wenlong Ren , Chenglong Pan , Zhongmei Zhou , Ying Yan , Longlong Zhang , Ceshi Chen
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, characterized by the poorest prognosis, and poses a significant threat to women's health. In this study, we identified two novel prieurianin-type limonoids extracted from Munronia henryi, one of which, named DHL-11, exhibited antitumor activity against TNBC cells. DHL-11 suppressed cell proliferation and migration, induced G2/M cell cycle arrest and apoptosis, and effectively increased the accumulation of reactive oxygen species (ROS) and cellular DNA damage in TNBC cells. Mechanistically, we found that DHL-11 binds to the non-catalytic pocket of IMPDH2 and disrupts the interaction between IMPDH2 and FANCI, leading to the degradation of the IMPDH2 protein. The decrease of IMPDH2 protein reduced guanine synthesis, increased ROS levels, and induced DNA damage. DHL-11 significantly inhibited the growth of breast cancer patient-derived organoids with high IMPDH2 expression. Furthermore, DHL-11 inhibited the growth and metastasis of TNBC xenografts in vivo with favorable biosafety profiles. Our findings highlight the potential of DHL-11 as a novel IMPDH2 degrader for the treatment of IMPDH2-positive TNBC.
{"title":"DHL-11, a novel prieurianin-type limonoid isolated from Munronia henryi, targeting IMPDH2 to inhibit triple-negative breast cancer","authors":"Yu Zhu , Zhibi Zhang , Xueqin Dai , Wenjing Liu , Jian Sun , Jialing Liu , Yuxin Zhao , Wenlong Ren , Chenglong Pan , Zhongmei Zhou , Ying Yan , Longlong Zhang , Ceshi Chen","doi":"10.1016/j.apsb.2025.10.031","DOIUrl":"10.1016/j.apsb.2025.10.031","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, characterized by the poorest prognosis, and poses a significant threat to women's health. In this study, we identified two novel prieurianin-type limonoids extracted from <em>Munronia henryi</em>, one of which, named DHL-11, exhibited antitumor activity against TNBC cells. DHL-11 suppressed cell proliferation and migration, induced G2/M cell cycle arrest and apoptosis, and effectively increased the accumulation of reactive oxygen species (ROS) and cellular DNA damage in TNBC cells. Mechanistically, we found that DHL-11 binds to the non-catalytic pocket of IMPDH2 and disrupts the interaction between IMPDH2 and FANCI, leading to the degradation of the IMPDH2 protein. The decrease of IMPDH2 protein reduced guanine synthesis, increased ROS levels, and induced DNA damage. DHL-11 significantly inhibited the growth of breast cancer patient-derived organoids with high IMPDH2 expression. Furthermore, DHL-11 inhibited the growth and metastasis of TNBC xenografts <em>in vivo</em> with favorable biosafety profiles. Our findings highlight the potential of DHL-11 as a novel IMPDH2 degrader for the treatment of IMPDH2-positive TNBC.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 1","pages":"Pages 287-304"},"PeriodicalIF":14.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941393","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}
Pub Date : 2026-01-01DOI: 10.1016/j.apsb.2025.11.026
Rui Li , Tian-Le Gao , Gang Ren , Lu-Lu Wang , Jian-Dong Jiang
Molecular mechanisms of chronic diseases are complicated, and it impedes drug target identification and subsequent drug discovery. We consider entropy increase in human body the root causes of chronic diseases. Accordingly, the inherent neg-entropic mechanisms, for instance the homeostatic mechanisms for metabolism, immunity, self-healing, etc., are true drug targets. Only very few molecules (such as proteins) are decisive for neg-entropy related functions, thus they are termed “head goose molecules” (HGMs) here. Identification of HGMs is key to activating neg-entropic mechanism(s), and drug intervention of the HGMs’ functions might reprogram the disease process through a neg-entropy mediated drug cloud (dCloud) effect, resulting in a treatment of both symptoms and root causes of the diseases. Thus, we recommend, for the first time, the “HGMs–neg-entropy–dCloud” axis as an important strategy for discovering new drugs. Clinically proven effective drugs that target HGMs are given as examples to illustrate the concept. Different from most of the single-target drugs that interrupt disease signal pathway(s), neg-entropy drugs treat chronic diseases through converting disorderliness to orderliness in the body of patients. We hope it to be helpful in future drug discovery for chronic diseases.
{"title":"Neg-entropy is the true drug target for chronic diseases","authors":"Rui Li , Tian-Le Gao , Gang Ren , Lu-Lu Wang , Jian-Dong Jiang","doi":"10.1016/j.apsb.2025.11.026","DOIUrl":"10.1016/j.apsb.2025.11.026","url":null,"abstract":"<div><div>Molecular mechanisms of chronic diseases are complicated, and it impedes drug target identification and subsequent drug discovery. We consider entropy increase in human body the root causes of chronic diseases. Accordingly, the inherent neg-entropic mechanisms, for instance the homeostatic mechanisms for metabolism, immunity, self-healing, etc., are true drug targets. Only very few molecules (such as proteins) are decisive for neg-entropy related functions, thus they are termed “head goose molecules” (HGMs) here. Identification of HGMs is key to activating neg-entropic mechanism(s), and drug intervention of the HGMs’ functions might reprogram the disease process through a neg-entropy mediated drug cloud (dCloud) effect, resulting in a treatment of both symptoms and root causes of the diseases. Thus, we recommend, for the first time, the “HGMs–neg-entropy–dCloud” axis as an important strategy for discovering new drugs. Clinically proven effective drugs that target HGMs are given as examples to illustrate the concept. Different from most of the single-target drugs that interrupt disease signal pathway(s), neg-entropy drugs treat chronic diseases through converting disorderliness to orderliness in the body of patients. We hope it to be helpful in future drug discovery for chronic diseases.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 1","pages":"Pages 231-238"},"PeriodicalIF":14.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941389","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}
Pub Date : 2026-01-01DOI: 10.1016/j.apsb.2025.11.030
Joshua Kramer , Eric Rohwer , Palaniappan Sethu , Min Xie , Timmy Lee , Victor Darley-Usmar , Jianhua Zhang
Mitochondria are essential for meeting cardiac metabolic demands and their dysfunction is associated with heart failure and is a key mediator of cardiac ischemia–reperfusion injury. Cardiomyocytes engage integrated mechanisms to maintain mitochondrial function; however, chronic stress or disease can overwhelm this capacity. The removal of damaged mitochondria is mediated by a process known as mitophagy, which, together with mitochondrial biogenesis, plays a key role in maintaining mitochondrial quality control. Maintenance of mitochondrial quality control was initially thought to be autonomously regulated within each cellular population with little exchange between cells. However, recently the phenomenon of transmitophagy has been identified in which damaged mitochondria are transferred to neighboring cells for degradation. This review discusses the current understanding of transmitophagy in the context of heart injury, aging and disease, with particular emphasis on exophers, migrasomes, and tunneling nanotubes as pathways mediating cell–cell communication between cardiomyocytes, macrophages and fibroblasts. We further discuss the potential of targeting transmitophagy for cardioprotection and highlight key unanswered questions and challenges. Addressing these gaps may reveal novel strategies to preserve mitochondrial homeostasis and improve the outcomes of patients with cardiovascular disease.
{"title":"Transmitophagy in the heart: An overview of molecular mechanisms and implications for pathophysiology","authors":"Joshua Kramer , Eric Rohwer , Palaniappan Sethu , Min Xie , Timmy Lee , Victor Darley-Usmar , Jianhua Zhang","doi":"10.1016/j.apsb.2025.11.030","DOIUrl":"10.1016/j.apsb.2025.11.030","url":null,"abstract":"<div><div>Mitochondria are essential for meeting cardiac metabolic demands and their dysfunction is associated with heart failure and is a key mediator of cardiac ischemia–reperfusion injury. Cardiomyocytes engage integrated mechanisms to maintain mitochondrial function; however, chronic stress or disease can overwhelm this capacity. The removal of damaged mitochondria is mediated by a process known as mitophagy, which, together with mitochondrial biogenesis, plays a key role in maintaining mitochondrial quality control. Maintenance of mitochondrial quality control was initially thought to be autonomously regulated within each cellular population with little exchange between cells. However, recently the phenomenon of transmitophagy has been identified in which damaged mitochondria are transferred to neighboring cells for degradation. This review discusses the current understanding of transmitophagy in the context of heart injury, aging and disease, with particular emphasis on exophers, migrasomes, and tunneling nanotubes as pathways mediating cell–cell communication between cardiomyocytes, macrophages and fibroblasts. We further discuss the potential of targeting transmitophagy for cardioprotection and highlight key unanswered questions and challenges. Addressing these gaps may reveal novel strategies to preserve mitochondrial homeostasis and improve the outcomes of patients with cardiovascular disease.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"16 1","pages":"Pages 1-12"},"PeriodicalIF":14.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941473","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}
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