Food frontiers最新文献

{"title":"Hawthorn Polyphenol Nanoparticles Alleviate Exercise-Induced Fatigue by Modulating Energy Metabolism and the Gut Microbiome in Mice","authors":"Chun Zhang,&nbsp;Yan Wang,&nbsp;Jiancheng Ma,&nbsp;Yihong Chen,&nbsp;Donglin Shi,&nbsp;Hao Wang,&nbsp;Xuedong Chang,&nbsp;Suwen Liu,&nbsp;Lina Dong","doi":"10.1002/fft2.70358","DOIUrl":"https://doi.org/10.1002/fft2.70358","url":null,"abstract":"<p>Polyphenols exert a variety of physiological effects; however, their utility is hampered by their limited bioavailability owing to their unstable nature. The bioavailability can be improved by encapsulating them in nanoparticles. In this study, hawthorn polyphenol nanoparticles (HPN) were prepared using an antisolvent method and layer-by-layer self-assembly, and the effects of HPN in alleviating exercise-induced fatigue in mice were investigated. The average size of HPN was 63.37 nm. The 1,1-diphenyl-2-trinitrophenylhydrazine (DPPH) radical scavenging activity and simulated intestinal fluid retention of HPN after 6 h was 65.08% and 98.91% higher, respectively, than those of the unencapsulated form. The retention time for HPN in mice extended to 19.7 h. The time to exhaustion during swimming against gravity increased from 114 s in the model group to 225 s in the HPN group (<i>p</i> &lt; 0.05). These effects were associated with reduced levels of fatigue-related metabolites, increased antioxidant enzyme activity, reduced hormone levels, and increased energy reserves (<i>p</i> &lt; 0.05). HPN alleviated fatigue by regulating the abundance and composition of the gut microbiota and the mRNA expression levels of <i>AMPK</i>, <i>PI3K</i>, <i>Akt</i>, and <i>mTOR</i>. In summary, this study demonstrates that HPN can achieve a sustained release of polyphenols and alleviate exercise-induced fatigue, providing a theoretical basis for its application in functional sports foods.</p>","PeriodicalId":73042,"journal":{"name":"Food frontiers","volume":"7 5","pages":""},"PeriodicalIF":6.3,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/fft2.70358","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148784662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plant-Derived Byproducts for Probiotic Encapsulation: A Composition–Microstructure–Function Review","authors":"Khadijat Oladayo Ganiyu,&nbsp;Jian Zhao","doi":"10.1002/fft2.70357","DOIUrl":"https://doi.org/10.1002/fft2.70357","url":null,"abstract":"<p>Probiotic delivery in foods is limited by viability losses during processing, storage, and gastrointestinal (GI) transit. Encapsulation may improve probiotic survival, but its effectiveness depends on both the carrier matrix and the surrounding food environment. This review examines plant-derived byproducts, including peels, pomaces, press cakes, pulp residues, and fiber-rich streams, as functional co-components of probiotic carrier systems. Rather than treating these materials as generic sustainability additives, we classify them according to dominant compositional fractions, including soluble polysaccharides, insoluble fibers, resistant starch, phenolic-rich extracts, and protein-containing fractions. A composition–microstructure–function framework is used to evaluate how byproduct composition, processing history, matrix properties, and stress conditions influence probiotic retention, release, and survival. Reported benefits are most interpretable when supported by matched comparators and physicochemical or microstructural measurements. Semiquantitative synthesis shows that byproduct effects vary across storage and GI conditions. Stronger mechanistic attribution is possible when viability improvements are reported alongside descriptors such as water activity, particle morphology, swelling, release behavior, and structural features. Translation remains constrained by feedstock variability, inconsistent reporting, limited comparator designs, regulatory uncertainty, fractionation scalability, and sensory or consumer-acceptance challenges. Overall, plant-derived byproducts show promise as candidate matrix components for food-grade probiotic delivery systems. Future progress will require safety qualification, specification-based material selection, evidence-weighted performance assessment, and validation in realistic food systems.</p>","PeriodicalId":73042,"journal":{"name":"Food frontiers","volume":"7 5","pages":""},"PeriodicalIF":6.3,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/fft2.70357","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148784661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Puerarin-Loaded Macrophage-Derived Exosomes for Experimental Atherosclerosis","authors":"Zijian Zou,&nbsp;Liangxing Tu,&nbsp;Ye Yang,&nbsp;Jianfang Feng,&nbsp;Yi Jin,&nbsp;Ruyue Yang,&nbsp;Meng Cheng","doi":"10.1002/fft2.70343","DOIUrl":"https://doi.org/10.1002/fft2.70343","url":null,"abstract":"<p>Atherosclerotic cardiovascular disease (AS) remains a leading global health concern. In this study, we investigated a macrophage-derived exosome-based delivery system for puerarin (Pue). The isolated vesicles were characterized by transmission electron microscopy, particle-size and zeta-potential analysis, and Western blot validation of extracellular vesicle-associated markers, including CD63, CD9, CD81, TSG101, and Alix, together with Calnexin as an endoplasmic-reticulum-associated negative/depletion marker. In vitro experiments showed that exosome-based delivery enhanced cellular uptake of puerarin and was associated with reduced oxidative-stress-related signals, decreased macrophage migratory activity, and reduced foam-cell-related readouts under the tested conditions. In vivo studies using an ApoE−/− mouse model showed that Pue–Exos reduced aortic plaque burden, promoted collagen deposition, and improved serum lipid-related indices. No obvious histopathological abnormalities were observed in major organs after treatment, suggesting preliminary in vivo tolerability. Mechanistic evaluation in C57BL/6 mice showed that treatment was associated with increased expression of HIF-1α, NF-κB, IL-6, IL-1β, CD68, and α-SMA under the present experimental conditions. Therefore, these findings are more appropriately interpreted as inflammation-associated signaling changes and remodeling-related responses, rather than definitive evidence of a uniformly suppressed inflammatory state or a confirmed anti-atherosclerotic mechanism. Taken together, these results suggest that macrophage-derived exosome-based delivery may improve the performance of puerarin in atherosclerosis-related experimental settings, although the underlying mechanism requires further clarification.</p>","PeriodicalId":73042,"journal":{"name":"Food frontiers","volume":"7 5","pages":""},"PeriodicalIF":6.3,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/fft2.70343","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148784062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Puerarin-Loaded Macrophage-Derived Exosomes for Experimental Atherosclerosis","authors":"Zijian Zou,&nbsp;Liangxing Tu,&nbsp;Ye Yang,&nbsp;Jianfang Feng,&nbsp;Yi Jin,&nbsp;Ruyue Yang,&nbsp;Meng Cheng","doi":"10.1002/fft2.70343","DOIUrl":"https://doi.org/10.1002/fft2.70343","url":null,"abstract":"<p>Atherosclerotic cardiovascular disease (AS) remains a leading global health concern. In this study, we investigated a macrophage-derived exosome-based delivery system for puerarin (Pue). The isolated vesicles were characterized by transmission electron microscopy, particle-size and zeta-potential analysis, and Western blot validation of extracellular vesicle-associated markers, including CD63, CD9, CD81, TSG101, and Alix, together with Calnexin as an endoplasmic-reticulum-associated negative/depletion marker. In vitro experiments showed that exosome-based delivery enhanced cellular uptake of puerarin and was associated with reduced oxidative-stress-related signals, decreased macrophage migratory activity, and reduced foam-cell-related readouts under the tested conditions. In vivo studies using an ApoE−/− mouse model showed that Pue–Exos reduced aortic plaque burden, promoted collagen deposition, and improved serum lipid-related indices. No obvious histopathological abnormalities were observed in major organs after treatment, suggesting preliminary in vivo tolerability. Mechanistic evaluation in C57BL/6 mice showed that treatment was associated with increased expression of HIF-1α, NF-κB, IL-6, IL-1β, CD68, and α-SMA under the present experimental conditions. Therefore, these findings are more appropriately interpreted as inflammation-associated signaling changes and remodeling-related responses, rather than definitive evidence of a uniformly suppressed inflammatory state or a confirmed anti-atherosclerotic mechanism. Taken together, these results suggest that macrophage-derived exosome-based delivery may improve the performance of puerarin in atherosclerosis-related experimental settings, although the underlying mechanism requires further clarification.</p>","PeriodicalId":73042,"journal":{"name":"Food frontiers","volume":"7 5","pages":""},"PeriodicalIF":6.3,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/fft2.70343","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148784225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Taurine and Metabolic Diseases: Molecular Mechanisms and Therapeutic Implications","authors":"Xiaojie Ma,&nbsp;Zhijian Rao,&nbsp;Lifang Zheng","doi":"10.1002/fft2.70354","DOIUrl":"https://doi.org/10.1002/fft2.70354","url":null,"abstract":"<p>Taurine (Tau) is a sulfur-containing amino acid prevalent in animal tissues and primarily acquired through dietary sources. Although previously categorized as a conditionally essential amino acid, its significant role in regulating redox balance, inflammatory responses, apoptosis, and metabolic homeostasis has garnered increasing recognition. Unlike focusing on a single disease, this article provides a comprehensive and up-to-date overview of the chemical properties, biological functions and supplementary safety of taurine, and particularly clarifies the protective effects and molecular mechanisms of taurine in metabolism-related diseases such as diabetes and its complications, obesity, non-alcoholic fatty liver disease, atherosclerosis, tumors, and aging, as well as metabolic disorder-related ocular and brain injury. Available evidence suggests that taurine acts not only through antioxidant, anti-inflammatory, and anti-apoptotic effects, but may also be involved in epigenetic regulation, bile acid–mediated lipid metabolism, and inter-organ interactions (e.g., gut-liver axis). While preclinical studies have demonstrated promising therapeutic potential, its clinical translation is currently hindered by a paucity of population-based evidence, ill-defined dose-response relationships (e.g., nonlinear characteristics in specific diseases), and its paradoxical role within specific tumor microenvironments. This article aims to provide a systematic theoretical reference for the in-depth research and potential clinical application of taurine in the prevention and treatment of metabolic diseases.</p>","PeriodicalId":73042,"journal":{"name":"Food frontiers","volume":"7 5","pages":""},"PeriodicalIF":6.3,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/fft2.70354","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148783998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Taurine and Metabolic Diseases: Molecular Mechanisms and Therapeutic Implications","authors":"Xiaojie Ma,&nbsp;Zhijian Rao,&nbsp;Lifang Zheng","doi":"10.1002/fft2.70354","DOIUrl":"https://doi.org/10.1002/fft2.70354","url":null,"abstract":"<p>Taurine (Tau) is a sulfur-containing amino acid prevalent in animal tissues and primarily acquired through dietary sources. Although previously categorized as a conditionally essential amino acid, its significant role in regulating redox balance, inflammatory responses, apoptosis, and metabolic homeostasis has garnered increasing recognition. Unlike focusing on a single disease, this article provides a comprehensive and up-to-date overview of the chemical properties, biological functions and supplementary safety of taurine, and particularly clarifies the protective effects and molecular mechanisms of taurine in metabolism-related diseases such as diabetes and its complications, obesity, non-alcoholic fatty liver disease, atherosclerosis, tumors, and aging, as well as metabolic disorder-related ocular and brain injury. Available evidence suggests that taurine acts not only through antioxidant, anti-inflammatory, and anti-apoptotic effects, but may also be involved in epigenetic regulation, bile acid–mediated lipid metabolism, and inter-organ interactions (e.g., gut-liver axis). While preclinical studies have demonstrated promising therapeutic potential, its clinical translation is currently hindered by a paucity of population-based evidence, ill-defined dose-response relationships (e.g., nonlinear characteristics in specific diseases), and its paradoxical role within specific tumor microenvironments. This article aims to provide a systematic theoretical reference for the in-depth research and potential clinical application of taurine in the prevention and treatment of metabolic diseases.</p>","PeriodicalId":73042,"journal":{"name":"Food frontiers","volume":"7 5","pages":""},"PeriodicalIF":6.3,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/fft2.70354","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148784226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cinnamaldehyde From Cinnamon as a Food-Derived Bioactive: Phytochemistry, Anticancer Mechanisms, Bioavailability, Nanoformulation and Safety","authors":"Gervason Moriasi,&nbsp;Sally Kamau,&nbsp;Gulnaz Seitimova,&nbsp;Shynar Zhumagaliyeva,&nbsp;Javad Sharifi-Rad,&nbsp;William N. Setzer,&nbsp;Daniela Calina","doi":"10.1002/fft2.70345","DOIUrl":"https://doi.org/10.1002/fft2.70345","url":null,"abstract":"<p>Cinnamaldehyde (CA), a bioactive compound derived from <i>Cinnamomum</i> species, has gained attention for its potential anticancer properties. Preclinical evidence suggests that CA exerts antitumor effects through multiple mechanisms, including the induction of apoptosis, modulation of redox homeostasis, inhibition of cell proliferation, and disruption of key signaling pathways such as PI3K/Akt/mTOR and MAPK/ERK. Its selective cytotoxicity toward cancer cells, with minimal effects on normal cells, further supports its therapeutic relevance. This review evaluated current evidence regarding the anticancer activity of CA, with a focus on its molecular mechanisms, structure–activity relationships, semisynthetic derivatives, and potential for combinatorial therapy. Relevant experimental and preclinical studies were examined to assess CA's efficacy in various cancer types, its pharmacokinetic limitations, and strategies for improved delivery, including nanoparticle and liposomal formulations. Findings indicate that CA affects several hallmarks of cancer, including apoptosis resistance, sustained proliferation, and metastasis. Enhanced anticancer activity has been reported when CA is used in combination with standard chemotherapeutic agents or other natural compounds. Nanotechnological approaches have demonstrated potential in overcoming CA's low bioavailability and rapid metabolism. CA shows promise as a multitargeted, low-toxicity compound suitable for adjuvant cancer therapy. Further investigation, particularly through clinical trials and advanced delivery systems, is required to confirm its efficacy and support clinical application.</p>","PeriodicalId":73042,"journal":{"name":"Food frontiers","volume":"7 5","pages":""},"PeriodicalIF":6.3,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/fft2.70345","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148784130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cinnamaldehyde From Cinnamon as a Food-Derived Bioactive: Phytochemistry, Anticancer Mechanisms, Bioavailability, Nanoformulation and Safety","authors":"Gervason Moriasi,&nbsp;Sally Kamau,&nbsp;Gulnaz Seitimova,&nbsp;Shynar Zhumagaliyeva,&nbsp;Javad Sharifi-Rad,&nbsp;William N. Setzer,&nbsp;Daniela Calina","doi":"10.1002/fft2.70345","DOIUrl":"https://doi.org/10.1002/fft2.70345","url":null,"abstract":"<p>Cinnamaldehyde (CA), a bioactive compound derived from <i>Cinnamomum</i> species, has gained attention for its potential anticancer properties. Preclinical evidence suggests that CA exerts antitumor effects through multiple mechanisms, including the induction of apoptosis, modulation of redox homeostasis, inhibition of cell proliferation, and disruption of key signaling pathways such as PI3K/Akt/mTOR and MAPK/ERK. Its selective cytotoxicity toward cancer cells, with minimal effects on normal cells, further supports its therapeutic relevance. This review evaluated current evidence regarding the anticancer activity of CA, with a focus on its molecular mechanisms, structure–activity relationships, semisynthetic derivatives, and potential for combinatorial therapy. Relevant experimental and preclinical studies were examined to assess CA's efficacy in various cancer types, its pharmacokinetic limitations, and strategies for improved delivery, including nanoparticle and liposomal formulations. Findings indicate that CA affects several hallmarks of cancer, including apoptosis resistance, sustained proliferation, and metastasis. Enhanced anticancer activity has been reported when CA is used in combination with standard chemotherapeutic agents or other natural compounds. Nanotechnological approaches have demonstrated potential in overcoming CA's low bioavailability and rapid metabolism. CA shows promise as a multitargeted, low-toxicity compound suitable for adjuvant cancer therapy. Further investigation, particularly through clinical trials and advanced delivery systems, is required to confirm its efficacy and support clinical application.</p>","PeriodicalId":73042,"journal":{"name":"Food frontiers","volume":"7 5","pages":""},"PeriodicalIF":6.3,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/fft2.70345","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148784129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Whole Wheat Flour Components Intervention Against Lead Toxicity: Impacts on Metal Bioavailability and Protection of the Intestinal Epithelial Barrier","authors":"Zhiyin Xiao,&nbsp;Tianhang Huang,&nbsp;Fengjiao Fan,&nbsp;Jian Ding,&nbsp;Xiaoyi Jiang,&nbsp;Xinyang Sun,&nbsp;Peng Li,&nbsp;Yong Fang","doi":"10.1002/fft2.70350","DOIUrl":"https://doi.org/10.1002/fft2.70350","url":null,"abstract":"<p>Consumption of whole wheat flour promotes lead excretion, yet the functional components reducing lead bioavailability and their protective mechanisms remain unclear. To identify these components and to validate whether their mechanism is related to protection of the intestinal barrier, this study established an in vitro model combining gastrointestinal simulated digestion, colonic fermentation, and Caco-2 intestinal epithelial cells. Results showed that dietary fiber and polyphenols are the key active components that synergistically reduce the bioavailability of lead to 3.90%. They exert a protective effect by maintaining intestinal barrier integrity, as evidenced by an increase in transepithelial electrical resistance of 22.66% and a reduction in cell monolayer permeability of 6.91% after 24 h compared to the lead group. Furthermore, they can alleviate oxidative stress, upregulate the expression of tight junction proteins, and improve intestinal barrier integrity to reduce lead absorption, thus providing a theoretical basis for dietary intervention in heavy metal exposure.</p>","PeriodicalId":73042,"journal":{"name":"Food frontiers","volume":"7 5","pages":""},"PeriodicalIF":6.3,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/fft2.70350","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148753458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting Microglial HDAC3 Enhances Aβ Clearance and Neuroprotection in APP/PS1 Mice: A Ketogenic Diet-Driven Strategy","authors":"Mingxiao Zheng,&nbsp;Gabriele Loers,&nbsp;Shengnan Lin,&nbsp;Hans-Christian Siebert,&nbsp;Qingpeng Wang,&nbsp;Ruiyan Zhang,&nbsp;Xuexing Zheng,&nbsp;Ning Zhang","doi":"10.1002/fft2.70346","DOIUrl":"https://doi.org/10.1002/fft2.70346","url":null,"abstract":"<p>Growing evidence suggests that impaired phagocytosis/autophagy and histone deacetylase 3 (HDAC3)-mediated microglial activation contribute significantly to Alzheimer's disease (AD) pathogenesis by promoting pathological protein aggregation. The ketogenic diet (KD) has demonstrated neuroprotective effects in AD, potentially through modulation of phagocytosis, autophagy, and inflammation. However, the underlying mechanisms remain unclear. Here, we report that a 12-week KD treatment ameliorated cognitive deficits, reduced amyloid-β (Aβ) deposition and tau hyperphosphorylation, and attenuated neuroinflammation in male APP/PS1 mice. Mechanistic studies revealed that these effects were associated with the modulation of microglial HDAC3. Specifically, KD downregulated microglial HDAC3, thereby enhancing Aβ phagocytosis, activating AMPK–ULK1-dependent autophagy, and restraining NLRP3 inflammasome activation, thereby promoting pathologic protein clearance. Given that β-hydroxybutyrate (BHB) is a major circulating ketone body produced during KD, we tested whether BHB recapitulates these effects in vitro. In Aβ-induced BV2 microglia, BHB mimicked the neuroprotective effects by downregulating HDAC3, which markedly enhanced Aβ clearance and suppressed inflammatory responses; these neuroprotective effects were largely abrogated by HDAC3 overexpression. To further confirm the causal role of microglial HDAC3 in mediating KD effects, we performed microglia-specific HDAC3 knockdown via AAV11-Iba1-shHDAC3. Notably, this manipulation enhanced both Aβ phagocytosis and autophagic degradation while inhibiting NLRP3 activation and contributed to neuroprotection. Overall, our findings suggest a novel mechanism by which KD exerts neuroprotective effects through modulation of the microglial HDAC3–AMPK–ULK1 axis and highlight microglia-specific HDAC3 inhibition as a promising therapeutic strategy for AD that simultaneously enhances Aβ clearance and attenuates neuroinflammation.</p>","PeriodicalId":73042,"journal":{"name":"Food frontiers","volume":"7 5","pages":""},"PeriodicalIF":6.3,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/fft2.70346","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148753459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}