The detection and identification of various phosphates are crucial in disease diagnostics. However, traditional detection techniques often require the development of multi-ion systems, and the complexity of sensor unit fabrication has limited the broad applications of sensor arrays. In this study, we report for the first-time the design of a colorimetric sensor using oxygen vacancy-regulated MoOx(2 ≤ x ≤ 3) nanosheets. By precisely modulating the concentration of introduced oxygen vacancies, the plasmonic resonance absorption peak of the MoOx nanosheets exhibited tunable shifts, thereby influencing their optical properties. The addition of phosphate ions with different configurations influenced the light absorption range and the plasmonic peak values of the oxygen vacancy-rich MoOx sensor array to various extents. Through statistical analysis methods, this sensing array effectively identified ten types of phosphates (i.e., ATP, ADP, AMP, PPi, Pi, UTP, GTP, GDP, GMP, and CTP). The sensor demonstrated excellent detection and discrimination capabilities in both quantitative identification and the recognition of mixed phosphates. The practical application of this sensor array was validated by precisely detecting phosphates in complex systems such as serum. Compared to the previous reports, the fabrication process of the oxygen vacancy-regulated MoOx nanosheets is simple, the discrimination detection effect is good, and it provides a new approach and method for the design and fabrication of highly efficient sensor arrays.
各种磷酸盐的检测和鉴定在疾病诊断中至关重要。然而，传统的检测技术往往需要开发多离子系统，并且传感器单元制造的复杂性限制了传感器阵列的广泛应用。在这项研究中，我们首次报道了使用氧空位调节的MoOx（2 ≤ x ≤ 3）纳米片设计的比色传感器。通过精确调制引入氧空位的浓度，MoOx纳米片的等离子共振吸收峰发生可调位移，从而影响其光学性质。不同构型磷酸盐离子的加入对富氧空位MoOx传感器阵列的光吸收范围和等离子体峰值有不同程度的影响。通过统计分析方法，该传感阵列有效识别出ATP、ADP、AMP、PPi、Pi、UTP、GTP、GDP、GMP、CTP等十种磷酸。该传感器在定量识别和混合磷酸盐识别方面均表现出优异的检测和识别能力。通过对血清等复杂系统中磷酸盐的精确检测，验证了该传感器阵列的实际应用。与以往报道相比，氧空位调节MoOx纳米片的制备工艺简单，识别检测效果好，为高效传感器阵列的设计和制造提供了新的途径和方法。
{"title":"Oxygen-Vacancy-Regulated Molybdenum oxide nanosheets for a Multi-Phosphate Discriminative colorimetric sensor array","authors":"Cheng Cheng, Xingying Li, Zhiwei Chen, Aiwu Wang, Fucong Lyu, Muhammad Humayun, Mohamed Bououdina","doi":"10.1016/j.jare.2026.01.025","DOIUrl":"https://doi.org/10.1016/j.jare.2026.01.025","url":null,"abstract":"The detection and identification of various phosphates are crucial in disease diagnostics. However, traditional detection techniques often require the development of multi-ion systems, and the complexity of sensor unit fabrication has limited the broad applications of sensor arrays. In this study, we report for the first-time the design of a colorimetric sensor using oxygen vacancy-regulated MoO<ce:inf loc=\"post\">x</ce:inf>(2 ≤ x ≤ 3) nanosheets. By precisely modulating the concentration of introduced oxygen vacancies, the plasmonic resonance absorption peak of the MoO<ce:inf loc=\"post\">x</ce:inf> nanosheets exhibited tunable shifts, thereby influencing their optical properties. The addition of phosphate ions with different configurations influenced the light absorption range and the plasmonic peak values of the oxygen vacancy-rich MoO<ce:inf loc=\"post\">x</ce:inf> sensor array to various extents. Through statistical analysis methods, this sensing array effectively identified ten types of phosphates (i.e., ATP, ADP, AMP, PPi, Pi, UTP, GTP, GDP, GMP, and CTP). The sensor demonstrated excellent detection and discrimination capabilities in both quantitative identification and the recognition of mixed phosphates. The practical application of this sensor array was validated by precisely detecting phosphates in complex systems such as serum. Compared to the previous reports, the fabrication process of the oxygen vacancy-regulated MoO<ce:inf loc=\"post\">x</ce:inf> nanosheets is simple, the discrimination detection effect is good, and it provides a new approach and method for the design and fabrication of highly efficient sensor arrays.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"1 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956612","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 : 2026-01-11DOI: 10.1016/j.jare.2026.01.021
Chaoying Wen, Yi Jiao, Zhaoran Wang, Tong Shi, Yan Wang, Jiahe Xu, Tiantian Deng, Guoqiang Zhang, Cheng Xiao
The dynamic crosstalk between N6-methyladenosine (m6A) RNA methylation and ferroptosis is pivotal for understanding disease pathogenesis. As the most abundant form of eukaryotic mRNA modification, m6A methylation guides RNA metabolism through writers, erasers, and readers. Ferroptosis, an iron-dependent and lipid peroxidation-driven form of cell death, occurs under conditions including dysregulated iron metabolism, compromised antioxidant defences, and lipid peroxidation.
{"title":"m6A methylation in ferroptosis regulation: mechanisms, targets, and therapeutic interventions","authors":"Chaoying Wen, Yi Jiao, Zhaoran Wang, Tong Shi, Yan Wang, Jiahe Xu, Tiantian Deng, Guoqiang Zhang, Cheng Xiao","doi":"10.1016/j.jare.2026.01.021","DOIUrl":"https://doi.org/10.1016/j.jare.2026.01.021","url":null,"abstract":"The dynamic crosstalk between N6-methyladenosine (m6A) RNA methylation and ferroptosis is pivotal for understanding disease pathogenesis. As the most abundant form of eukaryotic mRNA modification, m6A methylation guides RNA metabolism through writers, erasers, and readers. Ferroptosis, an iron-dependent and lipid peroxidation-driven form of cell death, occurs under conditions including dysregulated iron metabolism, compromised antioxidant defences, and lipid peroxidation.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"7 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956615","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 : 2026-01-10DOI: 10.1016/j.jare.2026.01.019
Bing Zhang, Wanida Phetsang, Sanjaya Kc, Mark S. Butler, Ruby Pelingon, Alysha G. Elliott, Maite Amado, Alejandra Gallardo-Godoy, Matthew A. Cooper, Mark A.T. Blaskovich
Introduction
Polymyxins are considered last-resort antibiotics for treating Gram-negative bacterial infections. The alarming global rise in polymyxin-resistant bacteria coupled with the slowness of conventional antimicrobial susceptibility testing methods leads to an unmet need for rapid susceptibility testing to facilitate timely and targeted therapeutic interventions.
Objectives
In this study, we aimed to develop novel polymyxin-derived fluorescent probes and improve the identification of polymyxin resistance by using these pathway-specific tools.
Methods
We designed, synthesized, and profiled a polymyxin-fluorophore derivative (PMX-NBD) with the small fluorophore NBD attached the central cyclic core of polymyxin via a triazole linker. We then applied PMX-NBD to develop RAPIDFC, a flow cytometry method that can rapidly and accurately profile polymyxin susceptibility of various Gram-negative pathogens.
Results
In contrast to many previously reported polymyxin probes, the fluorescent PMX-NBD retains the antimicrobial activity and profile of the parent polymyxin. Furthermore, we tested probe uptake in 49 strains encompassing E. coli, K. pneumoniae, P. aeruginosa, A. baumannii and S. aureus with a range of polymyxin sensitivity, leading to a susceptibility testing method RAPIDFC. Susceptibility to PMXB was defined by the difference between the Geometric Mean (GMean) of PMX-NBD fluorescence intensity at the two concentrations, with sensitive strains showing a greater variation compared to resistant strains. The RAPIDFC method is easy to implement and only requires 45 min compared to the broth microdilution method, which requires at least 24 h. However, the standard protocol failed to provide clear discrimination for A. baumannii, a key WHO-priority pathogen, necessitating a modified, species-specific approach for this organism.
Conclusions
The RAPIDFC method, based on the polymyxin-derived fluorescent probe, is fast and applicable to multiple species, making it a promising antimicrobial susceptibility method to guide appropriate therapy in the clinic. The case of A. baumannii demonstrates that species-specific resistance mechanisms may require tailored optimization of detection protocols.
{"title":"Rapid profiling of polymyxin B susceptibility in gram-negative bacteria with a novel polymyxin-derived fluorescent probe","authors":"Bing Zhang, Wanida Phetsang, Sanjaya Kc, Mark S. Butler, Ruby Pelingon, Alysha G. Elliott, Maite Amado, Alejandra Gallardo-Godoy, Matthew A. Cooper, Mark A.T. Blaskovich","doi":"10.1016/j.jare.2026.01.019","DOIUrl":"https://doi.org/10.1016/j.jare.2026.01.019","url":null,"abstract":"<h3>Introduction</h3>Polymyxins are considered last-resort antibiotics for treating Gram-negative bacterial infections. The alarming global rise in polymyxin-resistant bacteria coupled with the slowness of conventional antimicrobial susceptibility testing methods leads to an unmet need for rapid susceptibility testing to facilitate timely and targeted therapeutic interventions.<h3>Objectives</h3>In this study, we aimed to develop novel polymyxin-derived fluorescent probes and improve the identification of polymyxin resistance by using these pathway-specific tools.<h3>Methods</h3>We designed, synthesized, and profiled a polymyxin-fluorophore derivative (PMX-NBD) with the small fluorophore NBD attached the central cyclic core of polymyxin via a triazole linker. We then applied PMX-NBD to develop RAPID<sub>FC</sub>, a flow cytometry method that can rapidly and accurately profile polymyxin susceptibility of various Gram-negative pathogens.<h3>Results</h3>In contrast to many previously reported polymyxin probes, the fluorescent PMX-NBD retains the antimicrobial activity and profile of the parent polymyxin. Furthermore, we tested probe uptake in 49 strains encompassing <em>E. coli</em>, <em>K. pneumoniae</em>, <em>P. aeruginosa</em>, <em>A. baumannii</em> and <em>S. aureus</em> with a range of polymyxin sensitivity, leading to a susceptibility testing method RAPID<sub>FC</sub>. Susceptibility to PMXB was defined by the difference between the Geometric Mean (GMean) of PMX-NBD fluorescence intensity at the two concentrations, with sensitive strains showing a greater variation compared to resistant strains. The RAPID<sub>FC</sub> method is easy to implement and only requires 45 min compared to the broth microdilution method, which requires at least 24 h. However, the standard protocol failed to provide clear discrimination for<!-- --> <em>A. baumannii</em>, a key WHO-priority pathogen, necessitating a modified, species-specific approach for this organism.<h3>Conclusions</h3>The RAPID<sub>FC</sub> method, based on the polymyxin-derived fluorescent probe, is fast and applicable to multiple species, making it a promising antimicrobial susceptibility method to guide appropriate therapy in the clinic. The case of<!-- --> <em>A. baumannii</em> <!-- -->demonstrates that species-specific resistance mechanisms may require tailored optimization of detection protocols.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"1 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145949918","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}
Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality. Epigenetic dysregulation, particularly through methyltransferase METTL4, plays a critical role in HCC progression. METTL4 is known to catalyze m6Am methylation of mRNA, yet its pathological significance in liver cancer remains unclear.
Objective
This study aims to firstly investigate the role of METTL4 in the pathogenesis of HCC, and then to evaluate the antitumor efficacy of targeting METTL4 in inhibiting HCC growth and metastasis.
Methods
In a total of 802 postoperative HCC patients from four independent cohorts, we analyzed METTL4 expression in HCC tissues and its correlation with tumor staging and survival rates. Functional assays assessed the impact of METTL4 knockdown on HCC cell proliferation and metastasis, and patient-derived organoids (PDO) were used to evaluate the therapeutic efficacy of targeting METTL4. m6A-seq analyses identified GLI1 as a direct target of METTL4, investigating how METTL4-mediated m6Am modification affects GLI1 mRNA translation. Finally, we developed a siMETTL4-carrying nanoparticle and explored their efficacy in treating HCC in orthotopic and spontaneous liver tumor models.
Results
METTL4 was significantly upregulated in HCC tissues, correlating with higher tumor staging and poorer survival. Knockdown of METTL4 significantly inhibited HCC cell proliferation, migration, tumor growth, and lung metastasis. Meanwhile, targeting METTL4 effectively inhibited the growth of HCC PDO. METTL4-mediated m6Am modification enhanced GLI1 mRNA translation, with recognized target sites confirmed. Finally, siMETTL4-encapsulated nanoparticles effectively inhibited the growth and metastasis of orthotopic and spontaneous liver tumors.
Conclusions
Our findings highlight the role of METTL4-mediated m6Am modification in promoting HCC progression by enhancing GLI1 translation. Targeting METTL4 with siMETTL4-Nanoparticles represents a novel therapeutic strategy, bridging molecular insights in RNA epitranscriptomics with translational applications for HCC treatment.
{"title":"METTL4 enhances GLI1 translation through m6Am modification to promote tumor progression as a therapeutic target for hepatocellular carcinoma","authors":"Weijie Sun, Weiqi Dai, Chaobo Chen, Qian Qiu, Jianqing Chen, Jiaojiao Chen, Yueyue Li, Yuqi Liu, Dengyu Han, Wenhui Mo, Zishu Wang, Yihang Yuan, Xuanfu Xu","doi":"10.1016/j.jare.2026.01.009","DOIUrl":"https://doi.org/10.1016/j.jare.2026.01.009","url":null,"abstract":"<h3>Introduction</h3>Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality. Epigenetic dysregulation, particularly through methyltransferase METTL4, plays a critical role in HCC progression. METTL4 is known to catalyze m<sup>6</sup>Am methylation of mRNA, yet its pathological significance in liver cancer remains unclear.<h3>Objective</h3>This study aims to firstly investigate the role of METTL4 in the pathogenesis of HCC, and then to evaluate the antitumor efficacy of targeting METTL4 in inhibiting HCC growth and metastasis.<h3>Methods</h3>In a total of 802 postoperative HCC patients from four independent cohorts, we analyzed METTL4 expression in HCC tissues and its correlation with tumor staging and survival rates. Functional assays assessed the impact of METTL4 knockdown on HCC cell proliferation and metastasis, and patient-derived organoids (PDO) were used to evaluate the therapeutic efficacy of targeting METTL4. m<sup>6</sup>A-seq analyses identified GLI1 as a direct target of METTL4, investigating how METTL4-mediated m<sup>6</sup>Am modification affects GLI1 mRNA translation. Finally, we developed a siMETTL4-carrying nanoparticle and explored their efficacy in treating HCC in orthotopic and spontaneous liver tumor models.<h3>Results</h3>METTL4 was significantly upregulated in HCC tissues, correlating with higher tumor staging and poorer survival. Knockdown of METTL4 significantly inhibited HCC cell proliferation, migration, tumor growth, and lung metastasis. Meanwhile, targeting METTL4 effectively inhibited the growth of HCC PDO. METTL4-mediated m<sup>6</sup>Am modification enhanced GLI1 mRNA translation, with recognized target sites confirmed. Finally, siMETTL4-encapsulated nanoparticles effectively inhibited the growth and metastasis of orthotopic and spontaneous liver tumors.<h3>Conclusions</h3>Our findings highlight the role of METTL4-mediated m<sup>6</sup>Am modification in promoting HCC progression by enhancing GLI1 translation. Targeting METTL4 with siMETTL4-Nanoparticles represents a novel therapeutic strategy, bridging molecular insights in RNA epitranscriptomics with translational applications for HCC treatment.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"19 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937556","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 : 2026-01-06DOI: 10.1016/j.jare.2026.01.017
Laiming Zhang, Zengliang Jiang, Donghong Liu, Chengxiao Yu, Yi Wang, Haozhen Zhang, Jiaxiong Wu, Haibo Pan, Xingqian Ye, Shiguo Chen
Introduction
Sarcopenia, characterized by the progressive loss of muscle mass and function, may be alleviated by ellagic acid (EA) through its microbial metabolite urolithin A (Uro-A). However, the low in vivo conversion efficiency of EA to Uro-A limits its clinical utility.
Objectives
This study aimed to develop a gut microbiota-targeted dietary strategy to enhance Uro-A biosynthesis and improve muscle performance.
Methods
A combinatorial approach using EA and fructooligosaccharides (FOS) was applied in vivo to modulate microbial metabolism. Gut microbiota composition, urolithin profiles, and muscle performance were assessed. Mechanistic roles of key bacterial species were further explored.
Results
EA and FOS synergistically improved muscle endurance and strength by enhancing Uro-A production, compared with either intervention alone. Mechanistically, we identified a previously unrecognized two-step cooperative pathway: Bifidobacterium pseudolongum initiated EA metabolism by converting it to urolithin C (Uro-C), and while Enterococcus faecalis, identified here for the first time, catalyzed the conversion of Uro-C to Uro-A. This newly uncovered cross-feeding partnership between the two species proved essential for maximizing Uro-A biosynthesis and mediating the physiological benefits.
Conclusion
This study demonstrates a proof-of-concept strategy to boost gut microbial Uro-A biosynthesis through dietary modulation, providing a novel and cost-effective approach for sarcopenia prevention and management.
{"title":"Fructooligosaccharides and ellagic acid synergistically enhance muscular endurance via targeting gut microbial urolithin A biosynthesis","authors":"Laiming Zhang, Zengliang Jiang, Donghong Liu, Chengxiao Yu, Yi Wang, Haozhen Zhang, Jiaxiong Wu, Haibo Pan, Xingqian Ye, Shiguo Chen","doi":"10.1016/j.jare.2026.01.017","DOIUrl":"https://doi.org/10.1016/j.jare.2026.01.017","url":null,"abstract":"<h3>Introduction</h3>Sarcopenia, characterized by the progressive loss of muscle mass and function, may be alleviated by ellagic acid (EA) through its microbial metabolite urolithin A (Uro-A). However, the low <em>in vivo</em> conversion efficiency of EA to Uro-A limits its clinical utility.<h3>Objectives</h3>This study aimed to develop a gut microbiota-targeted dietary strategy to enhance Uro-A biosynthesis and improve muscle performance.<h3>Methods</h3>A combinatorial approach using EA and fructooligosaccharides (FOS) was applied <em>in vivo</em> to modulate microbial metabolism. Gut microbiota composition, urolithin profiles, and muscle performance were assessed. Mechanistic roles of key bacterial species were further explored.<h3>Results</h3>EA and FOS synergistically improved muscle endurance and strength by enhancing Uro-A production, compared with either intervention alone. Mechanistically, we identified a previously unrecognized two-step cooperative pathway: <em>Bifidobacterium pseudolongum</em> initiated EA metabolism by converting it to urolithin C (Uro-C), and while <em>Enterococcus faecalis,</em> identified here for the first time, catalyzed the conversion of Uro-C to Uro-A. This newly uncovered cross-feeding partnership between the two species proved essential for maximizing Uro-A biosynthesis and mediating the physiological benefits.<h3>Conclusion</h3>This study demonstrates a proof-of-concept strategy to boost gut microbial Uro-A biosynthesis through dietary modulation, providing a novel and cost-effective approach for sarcopenia prevention and management.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"44 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907652","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}
The high-fat diet (HFD) has complex health implications, shaped by the composition of macronutrients and food sources. However, existing dietary assessment tools lack the precision required for effective risk stratification.
Objectives
This study developed novel HFD scores to accurately characterize dietary patterns and examined their associations with total and cardiovascular disease (CVD) mortality, while also identifying relevant protein biomarkers.
Methods
Data from the UK Biobank and NHANES were utilized to develop a novel HFD scoring system incorporating both macronutrient ratios and quality indicators. Mortality associations were evaluated using Cox proportional hazards models, Kaplan-Meier analysis, and restricted cubic splines (RCS). Proteomic analysis was conducted to identify plasma proteins associated with mortality.
Results
The unhealthy HFD score showed a linear correlation with increased total and CVD mortality. In contrast, the healthy HFD score exhibited a U-shaped relationship with CVD mortality. On a 30-point HFD scale, individuals with low total mortality risk in the UK and US should maintain scores below 15, while those with low CVD risk in the UK should aim for scores between 10 and 15. An online HFD risk calculator was developed for practical application. Proteomic analysis revealed 48 proteins linked to total mortality and 153 proteins associated with CVD mortality, with significant enrichment in immune regulation and cardiovascular pathways. Machine learning models identified key predictors, such as EDA2R and NTproBNP, which demonstrated mediation effects of 12.92% and 13.86%, respectively.
Conclusion
These findings establish a precision nutrition framework that links HFD patterns, proteomic biomarkers, and mortality outcomes, offering actionable insights for clinical and public health intervention.
{"title":"High-fat diet score reveals total and cardiovascular mortality and identifies protein biomarkers in large cohorts","authors":"Xiaomin Li, Xiangju Kong, Shanpeng Liu, Chenyu Hou, Shali Cui, Xuan Zhu, Yue Guan, Songliu Hu, Changhao Sun, Yucun Niu","doi":"10.1016/j.jare.2026.01.016","DOIUrl":"https://doi.org/10.1016/j.jare.2026.01.016","url":null,"abstract":"<h3>Introduction</h3>The high-fat diet (HFD) has complex health implications, shaped by the composition of macronutrients and food sources. However, existing dietary assessment tools lack the precision required for effective risk stratification.<h3>Objectives</h3>This study developed novel HFD scores to accurately characterize dietary patterns and examined their associations with total and cardiovascular disease (CVD) mortality, while also identifying relevant protein biomarkers.<h3>Methods</h3>Data from the UK Biobank and NHANES were utilized to develop a novel HFD scoring system incorporating both macronutrient ratios and quality indicators. Mortality associations were evaluated using Cox proportional hazards models, Kaplan-Meier analysis, and restricted cubic splines (RCS). Proteomic analysis was conducted to identify plasma proteins associated with mortality.<h3>Results</h3>The unhealthy HFD score showed a linear correlation with increased total and CVD mortality. In contrast, the healthy HFD score exhibited a U-shaped relationship with CVD mortality. On a 30-point HFD scale, individuals with low total mortality risk in the UK and US should maintain scores below 15, while those with low CVD risk in the UK should aim for scores between 10 and 15. An online HFD risk calculator was developed for practical application. Proteomic analysis revealed 48 proteins linked to total mortality and 153 proteins associated with CVD mortality, with significant enrichment in immune regulation and cardiovascular pathways. Machine learning models identified key predictors, such as EDA2R and NTproBNP, which demonstrated mediation effects of 12.92% and 13.86%, respectively.<h3>Conclusion</h3>These findings establish a precision nutrition framework that links HFD patterns, proteomic biomarkers, and mortality outcomes, offering actionable insights for clinical and public health intervention.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"23 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907653","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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