Sarcopenia, characterized by the progressive age-related loss of skeletal muscle mass and function, is a primary driver of ambulatory dysfunction in older adults and lacks approved therapeutics. Although exercise has been shown to mitigate muscle aging through activation of peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α)-dependent mitochondrial biogenesis and oxidative metabolism, the practical implementation of exercise regimens is often constrained by age-related physical frailty and declining mobility. This limitation underscores the need for pharmacological approaches to replicate these advantageous adaptations.
Objectives
This study aimed to identify a potential therapeutic candidate that mimic the beneficial effects of PGC-1α overexpression and exercise intervention on aging-related sarcopenia and mitochondrial dysfunction.
Methods
We analyzed age-stratified muscle transcriptome data from various species and assessed the effects of muscle-specific PGC-1α overexpression on muscle aging. In silico transcriptome-based drug screening was conducted using the Connectivity Map (CMap). Subsequently, C2C12 myoblasts, young mice, aged Caenorhabditis elegans (C. elegans), and D-galactose (D-gal)-induced accelerated aging mice were administrated with celastrol to validate its therapeutic effect in counteracting aging-related muscle wasting and mitochondrial dysfunction. Celastrol’s efficacy and mechanisms were assessed through histological analysis, molecular biology, and transcriptomics analysis.
Results
Celastrol, a bioactive triterpenoid from Tripterygium wilfordii Hook. F., was identified as a top candidate that mimicked the gene signature induced by PGC-1α overexpression or exercise. Celastrol potentiated myogenic differentiation and mitochondrial bioenergetic capacity in vitro and in vivo with no side effects. In C. elegans, celastrol extended lifespan by 27.6% at 10 μM, concurrently reducing aging markers while restoring muscle integrity and mitochondrial morphology. Administration of celastrol also ameliorated aging-related muscle decline through boosting myogenic differentiation and mitochondrial oxidative metabolism in accelerated aging mice.
Conclusion
Collectively, these findings suggest celastrol as a pharmacological mimetic of exercise-induced mitochondrial rejuvenation, offering a translatable strategy to combat age-related muscle decline.
{"title":"In silico transcriptome-based drug screening identifies celastrol as a multi-species therapeutic agent against aging-related sarcopenia and mitochondrial dysfunction","authors":"Bangfu Wu, Jiaxin Liu, Zhaoyu Cui, Xingzhu Yin, Li Mo, Li Chen, Huimin Chen, Xuer Cheng, Yu Wang, Fangqu Liu, Chanhua Liang, Yuna Tian, Yuxia Chen, Xiaocui Liu, Yanyan Li, Ping Yao, Chao Gao, Yuhan Tang","doi":"10.1016/j.jare.2026.01.079","DOIUrl":"https://doi.org/10.1016/j.jare.2026.01.079","url":null,"abstract":"<h3>Introduction</h3>Sarcopenia, characterized by the progressive age-related loss of skeletal muscle mass and function, is a primary driver of ambulatory dysfunction in older adults and lacks approved therapeutics. Although exercise has been shown to mitigate muscle aging through activation of peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α)-dependent mitochondrial biogenesis and oxidative metabolism, the practical implementation of exercise regimens is often constrained by age-related physical frailty and declining mobility. This limitation underscores the need for pharmacological approaches to replicate these advantageous adaptations.<h3>Objectives</h3>This study aimed to identify a potential therapeutic candidate that mimic the beneficial effects of PGC-1α overexpression and exercise intervention on aging-related sarcopenia and mitochondrial dysfunction.<h3>Methods</h3>We analyzed age-stratified muscle transcriptome data<!-- --> <!-- -->from various species and assessed the effects of muscle-specific PGC-1α overexpression on muscle aging. <em>In silico</em> transcriptome-based drug screening was conducted using the Connectivity Map (CMap). Subsequently, C2C12 myoblasts, young mice, aged <em>Caenorhabditis elegans</em> (<em>C. elegans</em>), and D-galactose (D-gal)-induced accelerated aging mice were administrated with celastrol to validate its therapeutic effect in counteracting aging-related muscle wasting and mitochondrial dysfunction. Celastrol’s efficacy and mechanisms were assessed through histological analysis, molecular biology, and transcriptomics analysis.<h3>Results</h3>Celastrol, a bioactive triterpenoid from <em>Tripterygium wilfordii Hook. F.,</em> was identified as a top candidate that mimicked the gene signature induced by PGC-1α overexpression or exercise. Celastrol potentiated myogenic differentiation and mitochondrial bioenergetic capacity <em>in vitro</em> and <em>in vivo</em> with no side effects. In <em>C. elegans,</em> celastrol extended lifespan by 27.6% at 10 μM, concurrently reducing aging markers while restoring muscle integrity and mitochondrial morphology. Administration of celastrol also ameliorated aging-related muscle decline through boosting myogenic differentiation and mitochondrial oxidative metabolism in accelerated aging mice.<h3>Conclusion</h3>Collectively, these findings suggest celastrol as a<!-- --> <!-- -->pharmacological mimetic of exercise-induced mitochondrial rejuvenation, offering a translatable strategy to combat age-related muscle decline.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"1 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146101868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-02DOI: 10.1016/j.jare.2026.01.070
Suling Xu, Haitao Yang, Boris Minev, Wenxue Ma
Personalized nanovaccines represent advancing frontier in cancer immunotherapy by integrating patient-specific tumor antigens with biomimetic delivery systems to enhance immune activation, targeting precision and clinical efficacy. Biomimetic platforms including exosome-, red blood cell (RBC)-, and immune cell membrane-coated nanoparticles, as well as artificial antigen-presenting cell (aAPC) systems, recreate native biological interfaces to improve antigen presentation, macrophage polarization, and adaptive immune priming. Despite significant progress, major translational challenges remain, including incomplete mechanistic understanding, regulatory complexity, and manufacturing scalability. This review synthesizes recent advances in biomimetic and personalized nanovaccine design, highlighting clinical progress in lipid nanoparticle (LNP)-based vaccines such as BNT111 and mRNA-4157, emerging innate immune adjuvants including Toll-like receptor (TLR) and stimulator of interferon genes (STING) agonists, and rational combination strategies with immune checkpoint blockade. Key safety and quality consideration including immunotoxicity, off-target immune activation, and batch heterogeneity are critically evaluated alongside emerging engineering solutions. Finally, future directions integrating AI-guided neoantigen prediction, modular microfluidic manufacturing, and multi-omic biomarker frameworks are discussed to accelerate next generation cancer nanovaccine translation.
{"title":"Biomimetic and personalized nanovaccines in cancer immunotherapy: Design innovations, translational challenges, and future directions","authors":"Suling Xu, Haitao Yang, Boris Minev, Wenxue Ma","doi":"10.1016/j.jare.2026.01.070","DOIUrl":"https://doi.org/10.1016/j.jare.2026.01.070","url":null,"abstract":"Personalized nanovaccines represent advancing frontier in cancer immunotherapy by integrating patient-specific tumor antigens with biomimetic delivery systems to enhance immune activation, targeting precision and clinical efficacy. Biomimetic platforms including exosome-, red blood cell (RBC)-, and immune cell membrane-coated nanoparticles, as well as artificial antigen-presenting cell (aAPC) systems, recreate native biological interfaces to improve antigen presentation, macrophage polarization, and adaptive immune priming. Despite significant progress, major translational challenges remain, including incomplete mechanistic understanding, regulatory complexity, and manufacturing scalability. This review synthesizes recent advances in biomimetic and personalized nanovaccine design, highlighting clinical progress in lipid nanoparticle (LNP)-based vaccines such as BNT111 and mRNA-4157, emerging innate immune adjuvants including Toll-like receptor (TLR) and stimulator of interferon genes (STING) agonists, and rational combination strategies with immune checkpoint blockade. Key safety and quality consideration including immunotoxicity, off-target immune activation, and batch heterogeneity are critically evaluated alongside emerging engineering solutions. Finally, future directions integrating AI-guided neoantigen prediction, modular microfluidic manufacturing, and multi-omic biomarker frameworks are discussed to accelerate next generation cancer nanovaccine translation.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"97 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Obesity-associated non-alcoholic fatty liver disease (NAFLD) remains a global health burden with limited treatment options. Human milk fat substitutes (HMFS), designed to mimic the triacylglycerol structure of breast milk, have shown potential metabolic benefits. However, the mechanisms underlying their effects on hepatic lipid metabolism remain unclear.
Objectives
This study aims to evaluate the therapeutic effects of HMFS on established high fat diet-induced metabolic dysfunction and to delineate the lipid-mediated pathways involved.
Methods
A high-fat diet–induced obese mouse model was used to evaluate HMFS effects on metabolic parameters, liver histology, and lipid composition. Untargeted lipidomics identified candidate bioactive lipids. qPCR and Western blot were performed to assess hepatic gene and protein expression involved in lipid metabolism and signaling. Steatotic hepatocyte assays examined LPC 18:2 induced GPR119–AMPK activation. Molecular docking and molecular dynamics simulations were conducted to characterize LPC 18:2–GPR119 binding interactions.
Results
HMFS significantly reduced weight gain, hepatic triacylglycerols, and serum dyslipidemia, and improved liver enzyme profiles. Lipidomics revealed a marked elevation of LPC 18:2 alongside broad triacylglycerol reduction. HMFS upregulated enzymes involved in triacylglycerol hydrolysis and phospholipid remodeling, restoring hepatic GPR119–AMPK activation and promoting fatty acid oxidation over lipogenesis. Spearman correlation analysis revealed that LPC 18:2 levels were inversely correlated with obesity markers and positively correlated with GPR119–AMPK signaling. In vitro, LPC 18:2 replicated these effects in hepatocytes, reducing steatosis and enhancing AMPK phosphorylation. Computational analyses demonstrated stable LPC 18:2–GPR119 binding with favorable interaction energies.
Conclusion
HMFS alleviates diet-induced metabolic impairments in mice by enriching LPC 18:2, which activates GPR119–AMPK signaling to promote hepatic lipid catabolism. These findings provide mechanistic evidence supporting structured lipids as potential nutritional interventions for obesity-related liver disease.
{"title":"Human milk fat substitutes improve obesity-related NAFLD by enriching LPC 18:2 to activate hepatic GPR119–AMPK signaling","authors":"Yangzheng He, Jing Li, Zhigang Wen, Yong Sun, Liufeng Zheng, Hongyan Li, Zeyuan Deng","doi":"10.1016/j.jare.2026.01.083","DOIUrl":"https://doi.org/10.1016/j.jare.2026.01.083","url":null,"abstract":"<h3>Introduction</h3>Obesity-associated non-alcoholic fatty liver disease (NAFLD) remains a global health burden with limited treatment options. Human milk fat substitutes (HMFS), designed to mimic the triacylglycerol structure of breast milk, have shown potential metabolic benefits. However, the mechanisms underlying their effects on hepatic lipid metabolism remain unclear.<h3>Objectives</h3>This study aims to evaluate the therapeutic effects of HMFS on established high fat diet-induced metabolic dysfunction and to delineate the lipid-mediated pathways involved.<h3>Methods</h3>A high-fat diet–induced obese mouse model was used to evaluate HMFS effects on metabolic parameters, liver histology, and lipid composition. Untargeted lipidomics identified candidate bioactive lipids. qPCR and Western blot were performed to assess hepatic gene and protein expression involved in lipid metabolism and signaling. Steatotic hepatocyte assays examined LPC 18:2 induced GPR119–AMPK activation. Molecular docking and molecular dynamics simulations were conducted to characterize LPC 18:2–GPR119 binding interactions.<h3>Results</h3>HMFS significantly reduced weight gain, hepatic triacylglycerols, and serum dyslipidemia, and improved liver enzyme profiles. Lipidomics revealed a marked elevation of LPC 18:2 alongside broad triacylglycerol reduction. HMFS upregulated enzymes involved in triacylglycerol hydrolysis and phospholipid remodeling, restoring hepatic GPR119–AMPK activation and promoting fatty acid oxidation over lipogenesis. Spearman correlation analysis revealed that LPC 18:2 levels were inversely correlated with obesity markers and positively correlated with GPR119–AMPK signaling. <em>In vitro</em>, LPC 18:2 replicated these effects in hepatocytes, reducing steatosis and enhancing AMPK phosphorylation. Computational analyses demonstrated stable LPC 18:2–GPR119 binding with favorable interaction energies.<h3>Conclusion</h3>HMFS alleviates diet-induced metabolic impairments in mice by enriching LPC 18:2, which activates GPR119–AMPK signaling to promote hepatic lipid catabolism. These findings provide mechanistic evidence supporting structured lipids as potential nutritional interventions for obesity-related liver disease.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"58 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-02DOI: 10.1016/j.jare.2026.01.080
Jiangwei Xia, Jiajian Li, Siqi Chen, Tianpeng Chang, Yu Qian, Ou Wu, Yang Wu, Yinan Zhao, Junwei Hao, Lianmei Zhong
Introduction
Numerous studies have identified a close association between visceral adipose tissue mass (VAT) and neuropsychiatric disorders (NPDs). Both VAT and NPDs exhibit high heritability, yet their shared genetic architecture remains unclear.
Objectives
We sought to delineate genetic correlations, locus-level pleiotropy, causal effects, tissue/pathway context, and therapeutic hypotheses linking VAT with ten neuropsychiatric traits (nine NPDs plus cognitive function) using large-scale GWASs.
Methods
We conducted genetic correlation, polygenic overlap, colocalization, transcriptome-wide association (TWAS), bidirectional two-sample Mendelian randomization (MR), and pathway-tissue-phenotype-drug enrichment analyses.
Results
We uncovered significant genetic correlations and causal relationships between VAT and NPDs, with a notable bidirectional association pattern. Pleiotropy analysis identified 681 shared independent genomic risk loci, 74 of which are novel, and 19 are causal variants. These pleiotropic loci are predominantly expressed in hypothalamic and related brain regions, influencing lipid metabolism, neurodevelopment, neurotransmitter regulation, and synaptic plasticity via the HPA axis. TWAS analysis prioritized NUCKS1, MED27, LMF1, and YWHAB as novel candidate causal genes. Drug enrichment analysis highlighted 5-HT1A-targeting agents (e.g., vortioxetine) and calcium channel blockers (e.g., CACNA1C) as potential therapies for comorbid NPDs and obesity.
Conclusion
These findings support a shared genetic framework for brain-adipose crosstalk centered on hypothalamic-synaptic mechanisms and highlight potential therapeutic targets for comorbid management.
{"title":"Neural – adipose crosstalk: Shared genetic architecture of visceral fat and neuropsychiatric disorders","authors":"Jiangwei Xia, Jiajian Li, Siqi Chen, Tianpeng Chang, Yu Qian, Ou Wu, Yang Wu, Yinan Zhao, Junwei Hao, Lianmei Zhong","doi":"10.1016/j.jare.2026.01.080","DOIUrl":"https://doi.org/10.1016/j.jare.2026.01.080","url":null,"abstract":"<h3>Introduction</h3>Numerous studies have identified a close association between visceral adipose tissue mass (VAT) and neuropsychiatric disorders (NPDs). Both VAT and NPDs exhibit high heritability, yet their shared genetic architecture remains unclear.<h3>Objectives</h3>We sought to delineate genetic correlations, locus-level pleiotropy, causal effects, tissue/pathway context, and therapeutic hypotheses linking VAT with ten neuropsychiatric traits (nine NPDs plus cognitive function) using large-scale GWASs.<h3>Methods</h3>We conducted genetic correlation, polygenic overlap, colocalization, transcriptome-wide association (TWAS), bidirectional two-sample Mendelian randomization (MR), and pathway-tissue-phenotype-drug enrichment analyses.<h3>Results</h3>We uncovered significant genetic correlations and causal relationships between VAT and NPDs, with a notable bidirectional association pattern. Pleiotropy analysis identified 681 shared independent genomic risk loci, 74 of which are novel, and 19 are causal variants. These pleiotropic loci are predominantly expressed in hypothalamic and related brain regions, influencing lipid metabolism, neurodevelopment, neurotransmitter regulation, and synaptic plasticity via the HPA axis. TWAS analysis prioritized <em>NUCKS1, MED27, LMF1,</em> and <em>YWHAB</em> as novel candidate causal genes. Drug enrichment analysis highlighted 5-HT1A-targeting agents (e.g., vortioxetine) and calcium channel blockers (e.g., CACNA1C) as potential therapies for comorbid NPDs and obesity.<h3>Conclusion</h3>These findings support a shared genetic framework for brain-adipose crosstalk centered on hypothalamic-synaptic mechanisms and highlight potential therapeutic targets for comorbid management.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"1 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01DOI: 10.1016/j.jare.2026.01.075
Lin Chen, Haibo Li, Qingtain Zhu, Xingmeng Xu, Xinyi Liu, Xiaowu Dong, Chenchen Yuan, Weiwei Chen, Weiming Xiao, Zifan Ding, Keyan Wu, Bo Tu, Wei Li, Xiaoyu Zhu, Weijuan Gong, Guotao Lu, Dan Ji
Introduction
The necroptosis regulator PGAM5 drives a pathological cycle of mitochondrial dysfunction and necroptotic signaling, contributing to multi-organ injury and representing a potential therapeutic target. Despite its clinical relevance, few PGAM5-specific small-molecule inhibitors have been developed.
Objectives
We aimed to identify a safe and effective natural small-molecule inhibitor targeting PGAM5 as a novel therapeutic strategy.
Methods
Global PGAM5 knockout mice and pancreas-specific PGAM5 knockdown mice were used to clarify the regulatory role of PGAM5 in pancreatic injury in acute pancreatitis (AP). Subsequently, high-throughput screening of candidate compounds targeting PGAM5 was conducted based on the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Combined with molecular docking, in vitro binding experiments, and functional verification experiments, Plantainoside D (PD) was finally identified as a natural small-molecule inhibitor targeting PGAM5. Finally, the protective effect of PD was evaluated using preclinical models of various organ injuries.
Results
We identify PGAM5 as a critical mediator of pancreatic acinar cell (PAC) necrosis in AP. Genetic suppression of PGAM5 significantly mitigates PAC necrosis in both in vitro and in vivo AP models. Through high-throughput virtual screening of the TCMSP natural-product database, we identified PD, a phenylethanoid glycoside, as the first reported PGAM5-specific small-molecule inhibitor. By binding PGAM5, PD inhibits its phosphatase activity and prevents oligomerization, thereby restoring mitochondrial homeostasis and blocking necroptosis. Importantly, systemic PD administration demonstrated broad protective efficacy in multiple organ-injury models—including autoimmune hepatitis, acute kidney injury, myocardial ischemia − reperfusion, and lung fibrosis − as well as local efficacy in a pathological high intraocular pressure(ph-IOP) − induced retinal ganglion cell (RGC) injury model.
Conclusion
These findings establish PGAM5 as a druggable target in organ injury and identify PD as a natural compound with favorable safety and strong translational potential, providing a foundation for necroptosis-targeted therapeutic development.
{"title":"Screening and identification of a novel PGAM5-specific inhibitor for attenuating multi-organ injury","authors":"Lin Chen, Haibo Li, Qingtain Zhu, Xingmeng Xu, Xinyi Liu, Xiaowu Dong, Chenchen Yuan, Weiwei Chen, Weiming Xiao, Zifan Ding, Keyan Wu, Bo Tu, Wei Li, Xiaoyu Zhu, Weijuan Gong, Guotao Lu, Dan Ji","doi":"10.1016/j.jare.2026.01.075","DOIUrl":"https://doi.org/10.1016/j.jare.2026.01.075","url":null,"abstract":"<h3>Introduction</h3>The necroptosis regulator PGAM5 drives a pathological cycle of mitochondrial dysfunction and necroptotic signaling, contributing to multi-organ injury and representing a potential therapeutic target. Despite its clinical relevance, few PGAM5-specific small-molecule inhibitors have been developed.<h3>Objectives</h3>We aimed to identify a safe and effective natural small-molecule inhibitor targeting PGAM5 as a novel therapeutic strategy.<h3>Methods</h3>Global PGAM5 knockout mice and pancreas-specific PGAM5 knockdown mice were used to clarify the regulatory role of PGAM5 in pancreatic injury in acute pancreatitis (AP). Subsequently, high-throughput screening of candidate compounds targeting PGAM5 was conducted based on the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Combined with molecular docking, <em>in vitro</em> binding experiments, and functional verification experiments, Plantainoside D (PD) was finally identified as a natural small-molecule inhibitor targeting PGAM5. Finally, the protective effect of PD was evaluated using preclinical models of various organ injuries.<h3>Results</h3>We identify PGAM5 as a critical mediator of pancreatic acinar cell (PAC) necrosis in AP. Genetic suppression of PGAM5 significantly mitigates PAC necrosis in both <em>in vitro</em> and <em>in vivo</em> AP models. Through high-throughput virtual screening of the TCMSP natural-product database, we identified PD, a phenylethanoid glycoside, as the first reported PGAM5-specific small-molecule inhibitor. By binding PGAM5, PD inhibits its phosphatase activity and prevents oligomerization, thereby restoring mitochondrial homeostasis and blocking necroptosis. Importantly, systemic PD administration demonstrated broad protective efficacy in multiple organ-injury models—including autoimmune hepatitis, acute kidney injury, myocardial ischemia − reperfusion, and lung fibrosis − as well as local efficacy in a pathological high intraocular pressure(ph-IOP) − induced retinal ganglion cell (RGC) injury model.<h3>Conclusion</h3>These findings establish PGAM5 as a druggable target in organ injury and identify PD as a natural compound with favorable safety and strong translational potential, providing a foundation for necroptosis-targeted therapeutic development.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"253 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146101851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01DOI: 10.1016/j.jare.2026.01.082
Wenbo Zheng, Zepang Sun, Wei Wang, James Edward Han, Md Tauhidul Islam, Wencheng Li, Qingyu Yuan, Chuanli Chen, Sujuan Xi, Zihan Li, Xiaoyan Wang, Lin Wu, Wenjun Xiong, Tao Chen, Guoxin Li, Zhenhui Li, Jiang Yu, Yuming Jiang
Introduction
Tumor-associated neutrophils (TAN) critically promote gastric cancer progression. However, current assessment relies on invasive biopsies that preclude serial monitoring. Noninvasive tools to quantify TAN infiltration are urgently required.
Objectives
To develop and validate a noninvasive, CT-based ensemble machine learning radiomic biomarker for mapping TAN infiltration in gastric cancer, and to assess its utility for prognosis stratification and the prediction of response to anti-PD-1 immunotherapy.
Methods
In this multicenter study of 2,170 gastric cancer patients across eight cohorts, we developed EnmlbaRB, an ensemble machine-learning-based CT radiomic biomarker. Portal venous-phase scans were processed to extract features, with mRMR-Boruta algorithms identifying 11 radiomic signatures (six peritumoral and five intratumoral signatures). These were integrated via a five-tier heterogeneous stacking architecture supervised by the immunohistochemistry-derived CD66b + TAN status (high/medium/low). The validation spanned six independent cohorts, including 177 anti-PD-1-treated patients.
Results
External validation demonstrated robust performance: EnmlbaRB predicted TAN status with an AUC of 0.71 (95%CI: 0.65–0.78) and 80.74% specificity. Critically, TAN-Low patients exhibited significantly superior 5-year overall survival compared to TAN-High across all cohorts (e.g., SYSUCC cohort: 64.12% vs. 46.78%, p < 0.05). In the anti-PD-1 cohorts, the TAN-Low subgroups achieved 1.9-fold higher disease control rates (83.9% vs 44.1%; p < 0.001) and significantly prolonged median progression-free survival (>41.9 vs 6.2 months; HR = 0.162, p < 0.001), establishing clear clinical utility for immunotherapy stratification.
Conclusions
This study is the first clinically validated noninvasive solution for mapping the TAN infiltration status in gastric cancer. EnmlbaRB effectively stratified the patients based on survival outcomes and immunotherapy responsiveness. This paradigm empowers clinicians to personalize therapeutic sequencing based on evolving TAN biology, thereby addressing the critical need for adaptive treatment strategies for advanced gastric cancer management.
肿瘤相关中性粒细胞（TAN）对胃癌的进展有重要的促进作用。然而，目前的评估依赖于侵入性活检，排除了串行监测。目前迫切需要量化TAN浸润的无创工具。目的开发和验证一种无创的、基于ct的集成机器学习放射组学生物标志物，用于胃癌中TAN的浸润，并评估其在预后分层和预测抗pd -1免疫治疗反应中的应用。在这项跨8个队列的2170名胃癌患者的多中心研究中，我们开发了EnmlbaRB，一种基于机器学习的集成CT放射组学生物标志物。门静脉期扫描被处理以提取特征，mRMR-Boruta算法识别11个放射特征（6个肿瘤周围和5个肿瘤内特征）。这些通过免疫组织化学衍生的CD66b + TAN状态（高/中/低）监督的五层异质堆叠架构进行整合。验证跨越6个独立队列，包括177名抗pd -1治疗的患者。结果外部验证表明，EnmlbaRB预测TAN状态的AUC为0.71 (95%CI: 0.65-0.78)，特异性为80.74%。关键的是，在所有队列中，TAN-Low患者的5年总生存率明显优于TAN-High患者（例如，SYSUCC队列：64.12%对46.78%,p <； 0.05）。在抗pd -1队列中，TAN-Low亚组的疾病控制率提高了1.9倍（83.9% vs 44.1%; p <； 0.001），并显著延长了中位无进展生存期（>41.9 vs 6.2个月；HR = 0.162,p <； 0.001），为免疫治疗分层建立了明确的临床应用。结论本研究是第一个经临床验证的用于胃癌中TAN浸润状态的无创检测方法。EnmlbaRB基于生存结果和免疫治疗反应性有效地对患者进行分层。这种模式使临床医生能够基于不断发展的TAN生物学来个性化治疗测序，从而解决了晚期胃癌管理中适应性治疗策略的关键需求。
{"title":"Noninvasive imaging-based assessment of tumor-associated neutrophils for prognosis and immunotherapy response in gastric cancer: a multicenter study","authors":"Wenbo Zheng, Zepang Sun, Wei Wang, James Edward Han, Md Tauhidul Islam, Wencheng Li, Qingyu Yuan, Chuanli Chen, Sujuan Xi, Zihan Li, Xiaoyan Wang, Lin Wu, Wenjun Xiong, Tao Chen, Guoxin Li, Zhenhui Li, Jiang Yu, Yuming Jiang","doi":"10.1016/j.jare.2026.01.082","DOIUrl":"https://doi.org/10.1016/j.jare.2026.01.082","url":null,"abstract":"<h3>Introduction</h3>Tumor-associated neutrophils (TAN) critically promote gastric cancer progression. However, current assessment relies on invasive biopsies that preclude serial monitoring. Noninvasive tools to quantify TAN infiltration are urgently required.<h3>Objectives</h3>To develop and validate a noninvasive, CT-based ensemble machine learning radiomic biomarker for mapping TAN infiltration in gastric cancer, and to assess its utility for prognosis stratification and the prediction of response to anti-PD-1 immunotherapy.<h3>Methods</h3>In this multicenter study of 2,170 gastric cancer patients across eight cohorts, we developed EnmlbaRB, an ensemble machine-learning-based CT radiomic biomarker. Portal venous-phase scans were processed to extract features, with mRMR-Boruta algorithms identifying 11 radiomic signatures (six peritumoral and five intratumoral signatures). These were integrated via a five-tier heterogeneous stacking architecture supervised by the immunohistochemistry-derived CD66b + TAN status (high/medium/low). The validation spanned six independent cohorts, including 177 anti-PD-1-treated patients.<h3>Results</h3>External validation demonstrated robust performance: EnmlbaRB predicted TAN status with an AUC of 0.71 (95%CI: 0.65–0.78) and 80.74% specificity. Critically, TAN-Low patients exhibited significantly superior 5-year overall survival compared to TAN-High across all cohorts (e.g., SYSUCC cohort: 64.12% vs. 46.78%, p < 0.05). In the anti-PD-1 cohorts, the TAN-Low subgroups achieved 1.9-fold higher disease control rates (83.9% vs 44.1%; p < 0.001) and significantly prolonged median progression-free survival (>41.9 vs 6.2 months; HR = 0.162, p < 0.001), establishing clear clinical utility for immunotherapy stratification.<h3>Conclusions</h3>This study is the first clinically validated noninvasive solution for mapping the TAN infiltration status in gastric cancer. EnmlbaRB effectively stratified the patients based on survival outcomes and immunotherapy responsiveness. This paradigm empowers clinicians to personalize therapeutic sequencing based on evolving TAN biology, thereby addressing the critical need for adaptive treatment strategies for advanced gastric cancer management.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"67 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-01DOI: 10.1016/j.jare.2026.01.077
Junyan Zhuang, Ye Chen, Yi Zhang, Yongrui Hai, Renming Fan, Jiarui Dou, Xintong Lu, Wenhui Wang, Bingjie Zhang, Zhuang Hou, Lei Liang, Yang Liu, Gaofei Wei
Introduction
Glutamine is a key nutrient that supports tumor cell metabolism, biosynthesis, and proliferation. It also shapes the tumor microenvironment and modulates cell death pathways. Glutamine antagonists have emerged as effective therapeutic agents by both disrupting tumor energy metabolism and enhancing antitumor immune responses. However, recent evidence reveals a paradoxical effect: glutamine deprivation can induce PD-L1 expression on tumor cells, facilitating immune escape and reducing the efficacy of immunotherapies.
Objectives
This study aims to overcome the immune evasion triggered by glutamine deprivation by developing a dual-functional therapeutic strategy that enhances metabolic stress while simultaneously inhibiting PD-L1 expression. The ultimate goal is to strengthen antitumor immunity and improve therapeutic outcomes.
Methods
We designed and synthesized a novel prodrug, HB023, by covalently linking a glutamine metabolism inhibitor with JQ1, a well-characterized PD-L1 inhibitor. We evaluated the effects of HB023 on tumor cell pyroptosis, energy metabolism, PD-L1 expression, T cell-mediated cytotoxicity, and macrophage polarization using a combination of in vitro cell-based assays and in vivo tumor models.
Results
HB023 significantly enhanced glutamine starvation in tumor cells, leading to increased pyroptosis and restricted energy supply. It effectively downregulated PD-L1 expression, which restored T cell cytotoxic activity. Additionally, HB023 induced mitochondrial membrane remodeling in macrophages, promoting M1 polarization and thereby enhancing innate immune responses. These mechanisms cooperatively activated both adaptive and innate antitumor immunity, thereby conferring HB023 with superior antitumor efficacy compared with JQ1, JHU083, or their combination.
Conclusion
HB023 successfully addresses the challenge of glutamine deprivation-induced immune escape by integrating metabolic inhibition with immune checkpoint blockade. This dual-modulatory approach reprograms the tumor immune microenvironment and improves immunotherapeutic efficacy, representing a promising strategy for advancing cancer treatment.
{"title":"HB023: A glutamine antagonist prodrug boosting antitumor lmmunity via PD-L1 suppression and mitochondrial membrane remodeling","authors":"Junyan Zhuang, Ye Chen, Yi Zhang, Yongrui Hai, Renming Fan, Jiarui Dou, Xintong Lu, Wenhui Wang, Bingjie Zhang, Zhuang Hou, Lei Liang, Yang Liu, Gaofei Wei","doi":"10.1016/j.jare.2026.01.077","DOIUrl":"https://doi.org/10.1016/j.jare.2026.01.077","url":null,"abstract":"<h3>Introduction</h3>Glutamine is a key nutrient that supports tumor cell metabolism, biosynthesis, and proliferation. It also shapes the tumor microenvironment and modulates cell death pathways. Glutamine antagonists have emerged as effective therapeutic agents by both disrupting tumor energy metabolism and enhancing antitumor immune responses. However, recent evidence reveals a paradoxical effect: glutamine deprivation can induce PD-L1 expression on tumor cells, facilitating immune escape and reducing the efficacy of immunotherapies.<h3>Objectives</h3>This study aims to overcome the immune evasion triggered by glutamine deprivation by developing a dual-functional therapeutic strategy that enhances metabolic stress while simultaneously inhibiting PD-L1 expression. The ultimate goal is to strengthen antitumor immunity and improve therapeutic outcomes.<h3>Methods</h3>We designed and synthesized a novel prodrug, HB023, by covalently linking a glutamine metabolism inhibitor with JQ1, a well-characterized PD-L1 inhibitor. We evaluated the effects of HB023 on tumor cell pyroptosis, energy metabolism, PD-L1 expression, T cell-mediated cytotoxicity, and macrophage polarization using a combination of <em>in vitro</em> cell-based assays and <em>in vivo</em> tumor models.<h3>Results</h3>HB023 significantly enhanced glutamine starvation in tumor cells, leading to increased pyroptosis and restricted energy supply. It effectively downregulated PD-L1 expression, which restored T cell cytotoxic activity. Additionally, HB023 induced mitochondrial membrane remodeling in macrophages, promoting M1 polarization and thereby enhancing innate immune responses. These mechanisms cooperatively activated both adaptive and innate antitumor immunity, thereby conferring HB023 with superior antitumor efficacy compared with JQ1, JHU083, or their combination.<h3>Conclusion</h3>HB023 successfully addresses the challenge of glutamine deprivation-induced immune escape by integrating metabolic inhibition with immune checkpoint blockade. This dual-modulatory approach reprograms the tumor immune microenvironment and improves immunotherapeutic efficacy, representing a promising strategy for advancing cancer treatment.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"34 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146101869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-30DOI: 10.1016/j.jare.2026.01.057
Jimyeong Park, Minseo Kim, Changhyun Jin, Kyu Hyoung Lee, Myung Sik Choi
{"title":"Simultaneous engineering of the surface (oxygen/amorphous carbon) and interface (amorphous carbon/ZnO) of ZnO using a one-spoon amorphous carbon deposition technique","authors":"Jimyeong Park, Minseo Kim, Changhyun Jin, Kyu Hyoung Lee, Myung Sik Choi","doi":"10.1016/j.jare.2026.01.057","DOIUrl":"https://doi.org/10.1016/j.jare.2026.01.057","url":null,"abstract":"","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"43 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146089748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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