Journal of Nutritional Biochemistry最新文献

{"title":"Gut microbiome-targeted bile acid metabolomics integration reveals dietary cordycepin alleviates NAFLD in diabetic mice by enriching Clostridia and affecting the PXR/Sult2a1/CA7S.","authors":"Ying Meng, Mengqian Dun, Xinyuan Liu, Weibo Chen, Zhongming Zhang, Shengyu Lu, Guoying Zhang, Jianya Ling","doi":"10.1016/j.jnutbio.2026.110500","DOIUrl":"https://doi.org/10.1016/j.jnutbio.2026.110500","url":null,"abstract":"<p><p>Non-alcoholic fatty liver disease (NAFLD) frequently coexists with type 2 diabetes mellitus (T2DM), posing a significant metabolic disorder with limited dietary intervention options. Cordycepin, a food‑derived nucleoside from the edible fungus Cordyceps militaris, exhibits hypoglycemic and hypolipidemic effects, but its role in T2DM combined with NAFLD remains unknown. Here, we established a mouse model of T2DM combined with NAFLD in male KM mice using high-fructose and high‑fat diet, and streptozotocin. Both cordycepin (COR) and Cordyceps militaris water extract (CWE) attenuated glucose intolerance, dyslipidemia, hepatic steatosis, liver injury, inflammatory response and oxidative stress, with cordycepin showing superior efficacy. Multi‑omics analysis revealed that cordycepin uniquely reshaped the gut microbiota by significantly enriching the c__Clostridia, including g__Acetatifactor, g__Anaerovorax, g__Monoglobus, s__Acutalibacter_muris, and further affected liver metabolism, which was characterized by enrichment of bile acid metabolism-related pathways. Targeted bile acid metabolomics demonstrated that cordycepin specifically promoted the production of cholic acid‑7‑sulfate (CA7S), a gut‑restricted secondary bile acid, through activation of the hepatic PXR/Sult2a1 pathway. Notably, integrated correlation analysis revealed a significant positive association between CA7S and c__Clostridia (e.g., g__Monoglobus, g__Lachnoclostridium, and g__Anaerovorax), suggesting that cordycepin enhances CA7S production by enriching these Clostridia members. And CA7S activated TGR5 to stimulate glucagon‑like peptide‑1 (GLP‑1) secretion, thereby improving glucose and lipid homeostasis. Therefore, these findings demonstrate that dietary cordycepin improves T2DM combined with NAFLD by modulating gut microbiota, particularly Clostridia, and affecting the PXR/Sult2a1/CA7S/GLP‑1 pathway, thereby exerting beneficial effects on glucose and lipid homeostasis.</p>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":" ","pages":"110500"},"PeriodicalIF":5.2,"publicationDate":"2026-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148897534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of maternal docosahexaenoic acid intake on febrile seizures and increased seizure susceptibility after febrile seizures: Study using mouse models and human samples.","authors":"Masahiro Ishii, Tatsuto Nakane, Shinji Kawano, Iroha Okuda, Ayako Senju, Shunsuke Araki, Kouichi Itoh, Takashi Tominaga, Tomohiro Yonezawa, Mayumi Tsuji, Yasuhiro Ishihara","doi":"10.1016/j.jnutbio.2026.110499","DOIUrl":"https://doi.org/10.1016/j.jnutbio.2026.110499","url":null,"abstract":"<p><p>The effects of docosahexaenoic acid (DHA) on seizures and epilepsy remain controversial and appear to depend on the specific context. In this study, we investigated the effects of maternal DHA intake on febrile seizures and post-febrile seizure susceptibility. Mice exposed to DHA during pregnancy showed considerably higher brain DHA and 17β-estradiol (E2) levels than controls, along with a marked delay in the onset of febrile seizures. These effects were abolished by letrozole, an inhibitor of cytochrome P450 family 19 subfamily A, suggesting that the DHA-induced increase in E2 reduces susceptibility to febrile seizures. Maternal DHA intake also suppressed neuroinflammation after febrile seizures and reduced seizure susceptibility later in life following pentylenetetrazol treatment. These protective effects also required E2 synthesis, as they were abolished by letrozole, indicating that the DHA-induced increase in E2 reduces long-term seizure susceptibility even after febrile seizures have occurred. In children with febrile seizures, serum DHA and E2 levels were markedly lower than those in controls. In addition, serum interleukin-1 beta levels were inversely correlated with serum E2 concentrations. Together, DHA can delay febrile seizure onset and attenuate inflammation in an E2-dependent manner. Maternal DHA intake during pregnancy may therefore contribute to healthy brain development in children.</p>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":" ","pages":"110499"},"PeriodicalIF":5.2,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Complanatuside Ameliorates Renal Injury and Fibrosis in Chronic Kidney Disease by Inhibiting Tubular Cell Apoptosis via Activation of KLK1/BDKRB2.","authors":"Jing Gao, Rui-Zhi Tan, Ke Deng, Bing-Hong Peng, Jian Liu, Li Wang","doi":"10.1016/j.jnutbio.2026.110490","DOIUrl":"https://doi.org/10.1016/j.jnutbio.2026.110490","url":null,"abstract":"<p><strong>Background: </strong>Chronic kidney disease (CKD) is characterized by renal fibrosis as a key pathological feature. Total flavonoids extracted from Astragalus complanatus can effectively alleviate renal fibrosis. However, the anti-fibrotic effect and the underlying specific mechanisms of its main active component, Complanatuside (CPT), remain unclear. This study aims to investigate the role of CPT on apoptosis and fibrosis of kidney in CKD, and the underlying mechanism.</p><p><strong>Methods: </strong>The protective effects of CPT against CKD were investigated using mouse and cell models of CKD, and its key targets and mechanisms were identified.</p><p><strong>Results: </strong>The results showed that CPT ameliorated renal fibrosis in UUO mice and TGF-β1-induced fibrosis in HK2 cells. Notably, our single-cell RNA sequencing analysis revealed that CPT significantly reduced failed-repair tubular cells and inhibited apoptosis, accompanied by marked activation of KLK1 gene expression. We found that CPT binds to KLK1, activates its expression, reduces PTEC apoptosis, and thereby attenuates renal fibrosis. In line with this, in vitro studies showed that overexpressing KLK1 reduced TGF-β1-induced fibrosis and apoptosis, whereas knocking down KLK1 reversed CPT's renal protective effect. Further bioinformatics analysis indicated that KLK1 promotes BDKRB2 expression. Knocking down BDKRB2 exacerbated TGF-β1-induced fibrosis and apoptosis. Additionally, when investigating the relationship between KLK1 and BDKRB2, we found a direct interaction between them. Furthermore, downregulation of BDKRB2 counteracted the inhibitory effects of KLK1 overexpression on cell apoptosis and renal fibrosis.</p><p><strong>Conclusion: </strong>This study reveals that CPT binds to KLK1, promotes BDKRB2 expression, thereby reducing PTEC apoptosis and improving renal fibrosis.</p>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":" ","pages":"110490"},"PeriodicalIF":5.2,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sn-2 palmitate-enriched structured lipids attenuate early aging phenotypes in senescence-accelerated mice.","authors":"Rie Tsutsumi, Sae Tanaka, Yui Funatsu, Yoshihiro Meta, Yuna Izumi-Mishima, Kazuhiro Nomura, Hiroshi Sakaue","doi":"10.1016/j.jnutbio.2026.110491","DOIUrl":"https://doi.org/10.1016/j.jnutbio.2026.110491","url":null,"abstract":"<p><p>Aging is characterized by progressive cognitive decline and metabolic dysregulation, contributing to increased vulnerability to age-related disorders. β-position palmitic acid -containing structured lipids (sn-2 palmitate), naturally enriched in human milk fat, have been reported to modulate inflammation and lipid metabolism. However, whether sn-2 palmitate-rich lipids exert beneficial effects beyond early development, particularly in the context of aging-related decline, remains unclear; further, its effects in aged populations or senescence models remain largely unknown. Therefore, we investigated the potential anti-aging effects of sn-2 palmitate-enriched lipid in senescence-accelerated mouse prone 8 (SAMP8)-a model of age-related functional decline. Eight-week-old SAMP8 mice were fed a sn-2 palmitate-enriched lipid supplemented diet for eight weeks. Behavioral tests, hippocampal biochemical analyses, and histological assessments were performed. sn-2 palmitate-enriched lipid supplementation significantly improved cognitive performance and reduced hippocampal expression of senescence markers (p16, p21) and pro-inflammatory cytokines (IL-6, TNF-α). Furthermore, sn-2 palmitate enhanced NAD⁺/NADH ratios and increased Sirt1/3 deacetylase activities, accompanied by upregulation of mitochondrial biogenesis-related factors (PGC-1α, NRF1, TFAM). These findings suggest that sn-2 palmitate-enriched lipid may attenuate aging-associated cognitive and physiological decline through modulation of NAD⁺ metabolism and mitochondrial function.</p>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":" ","pages":"110491"},"PeriodicalIF":5.2,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148887766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Indole-3-acetic acid alleviates intestinal failure associated liver disease via the miR-216a-5p/LRH-1 axis.","authors":"Shuai Liu, Longchang Huang, Sirui Liu, Xin Qi, Gulisudumu Maitiabula, Xinying Wang","doi":"10.1016/j.jnutbio.2026.110488","DOIUrl":"https://doi.org/10.1016/j.jnutbio.2026.110488","url":null,"abstract":"<p><strong>Background: </strong>Long-term total parenteral nutrition can cause intestinal failure-associated liver disease (IFALD). Gut microbiota-derived indole-3-acetic acid (IAA) has been linked to liver disease, but mechanisms remain unclear. This study aimed to verify the protective role of Lactobacillus reuteri and IAA in IFALD and to investigate whether IAA acts through the miR-216a-5p/LRH-1 axis.</p><p><strong>Methods: </strong>We used male C57BL/6 mice and established a total parenteral nutrition (TPN) model following dextran sulfate sodium (DSS) administration. Differential bacterial species and metabolites were screened and validated through multi-omics analyses and fecal microbiota transplantation (FMT) experiments. Downstream miRNAs and mRNAs were identified by transcriptome and miRNA sequencing. Gene overexpression and knockdown were performed using an adeno-associated virus (AAV) or plasmid vectors. Histopathological staining and serological indicators were used to assess the pathological changes in each group.</p><p><strong>Results: </strong>We found that the abundance of Lactobacillus reuteri (L. reuteri) in IFALD was significantly reduced, and supplementation with L. reuteri protected against liver injury in IFALD. IAA, a tryptophan metabolite of L. reuteri, can alleviated hepatic steatosis and metabolic disorders in an IFALD mouse model by downregulating miR-216a-5p in hepatocytes, which in turn promotes the expression of liver receptor homologue-1 (LRH-1, Nr5a2). However, the overexpression of miR-216a-5p abolished the hepatoprotective effects of IAA.</p><p><strong>Conclusions: </strong>Overall, our study identified IAA as important mediator for alleviating liver injury via the miR-216a-5p-LRH-1 axis, providing evidence for the diagnosis and treatment of IFALD.</p>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":" ","pages":"110488"},"PeriodicalIF":5.2,"publicationDate":"2026-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148794452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Salidroside and Apigenin attenuate bone resorption in ovariectomized mice and osteoclasts via Sema3A/Nrp1/PlexinA1 pathway.","authors":"Yueyi Zhang, Hanfei Shi, Xuan Dai, Gaiyue Yue, Haochen Guo, Ruiqiong Liang, Jiyuan Yin, Tianshu Xu, Rui Li, Sihua Gao, Vasily Sukhorukov, Ze Zhong Wang, Lili Wang, Gang Zhou, Dongwei Zhang","doi":"10.1016/j.jnutbio.2026.110485","DOIUrl":"https://doi.org/10.1016/j.jnutbio.2026.110485","url":null,"abstract":"<p><p>Osteoporosis is becoming one of the major global health concerns with accelerating of the aging population and there is an urgent need for novel countermeasures. Salidroside (SAL) and Apigenin (AP) are compounds identified in Ligustri Lucidi Fructus (LLF), a dietary herb that has historically been used and is currently used in osteoporosis management. However, their effects on bone loss remain largely unexplored. To this end, ovariectomized (OVX) mice and osteoclasts differentiated from RAW 264.7 were used to establish the osteoporotic model in vivo and in vitro. We found that SAL and AP treatments reduce the numbers of TRAP-positive cells, F-actin rings and bone resorption pits, and suppress the expression levels of c-Fos, Nfatc1 and Ctsk in osteoclasts. In addition, SAL and AP can improve bone quality and decrease serum levels of CTX-1 and TRAP-5b in OVX mice. These compounds further increase the expression levels of Sema3A, Nrp1 and PlexinA1 in osteoclasts and osteoporotic animals. In conclusion, SAL and AP limit osteoclastic bone resorption to ameliorate bone quality via upregulation of the Sema3A/Nrp1/PlexinA1 signaling pathway, providing a novel strategy for osteoporosis management.</p>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":" ","pages":"110485"},"PeriodicalIF":5.2,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148794510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HACD3 Integrates Central Leptin Sensitivity and Peripheral Thermogenesis to Oppositely Regulate Energy Balance.","authors":"Qindan Du, Zhen Han, Xiao Jian, Bingqian Sun, Sitao Chen, Wei Luo, Xiaoying Wang","doi":"10.1016/j.jnutbio.2026.110487","DOIUrl":"https://doi.org/10.1016/j.jnutbio.2026.110487","url":null,"abstract":"<p><p>The enzyme 3-hydroxyacyl-CoA-dehydratase 3 (HACD3) is involved in fatty acid synthesis, but its systemic role in metabolism is unknown. This study investigated the physiological function of HACD3 in energy homeostasis. Systemic HACD3 deficiency protected mice from diet-induced obesity by increasing energy expenditure and activating adipose thermogenesis. Conversely, deleting HACD3 specifically in leptin receptor-expressing neurons caused obesity, hyperphagia, and leptin resistance. In adipocytes, HACD3 cell-autonomously repressed thermogenesis by forming a complex with Keratin 1 (KRT1), which sequestered thermogenic transcription factors and maintained repressive chromatin. HACD3 ablation disrupted this complex, enabling nuclear translocation of PPARγ/PGC-1α and increasing transcription of thermogenic genes. In neurons, HACD3 is required for leptin receptor stability and signalling. HACD3 acts as a critical, tissue-specific regulator that simultaneously governs both sides of the energy balance equation-suppressing energy expenditure in adipose tissue while facilitating anorexigenic signalling in the brain. This dual function identifies HACD3 as a novel, multifaceted target for therapeutic intervention in metabolic disorders.</p>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":" ","pages":"110487"},"PeriodicalIF":5.2,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148794479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of the gut-brain axis and polyphenolic compounds in glioblastoma.","authors":"Bhavana Agnihotram, Iris Mutiu, Hannah Chiou, Kelly McGowen, Candice Mazewski","doi":"10.1016/j.jnutbio.2026.110484","DOIUrl":"https://doi.org/10.1016/j.jnutbio.2026.110484","url":null,"abstract":"<p><p>Polyphenols are metabolites derived from plant-based sources studied in cancer research for their anti-inflammatory, antioxidant, and antiproliferative properties. While previous studies have focused more on their impact on gastrointestinal diseases like inflammatory bowel disease and malignancies such as colon cancer, there is less attention on their role in neurological diseases and malignancies more distant from the gastrointestinal tract, like brain cancer. Recent work indicates potential for polyphenols to beneficially modulate the gut microbiome and improve neurological disorders through the gut-brain axis. Glioblastoma (GBM), classified as a grade 4 brain tumor by the World Health Organization, poses significant challenges with inefficient conventional treatments that yield a low five-year survival rate. Recent meta-analyses demonstrate the potential of various plant foods to reduce the risk of glioma. However, specific dietary recommendations for brain cancer remain elusive, and the mechanisms of action of plant foods and their compounds, as well as their impact through the gut-brain axis, must still be explored. This review will discuss the impact of polyphenols on the gut-brain axis and analyze the potential benefits of implementing them as preventive and therapeutic GBM interventions with relation to the gut microbiome.</p>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":" ","pages":"110484"},"PeriodicalIF":5.2,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148794499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"miR-1a-3p impairs β-cell function in male offspring via disrupted NBR1-dependent mitochondrial function but not apoptosis after maternal high-saturated-fat diet in mice.","authors":"Chenchen Geng, Yansong Zhang, Jiaxin Zhao, Jiaqi Li, Lingfeng Dan, Qi Chen, Yue Zhang, Junwen Zheng, Romano Regazzi, Youbin Liu, Huimin Lu","doi":"10.1016/j.jnutbio.2026.110480","DOIUrl":"10.1016/j.jnutbio.2026.110480","url":null,"abstract":"<p><p>Early-life maternal high-saturated fat (HSF) exposure increases offspring susceptibility to type 2 diabetes, but mechanisms linking it to β-cell dysfunction remain poorly defined. This study aimed to identify key miRNAs mediating this programming and evaluate their therapeutic potential. Female mice were fed control, high-lard, or high-palm oil diets during gestation and lactation. Islets from adult male offspring were isolated for miRNA sequencing to identify candidates. β-cell-specific overexpression of miR-1a-3p was achieved via AAV8-Ins1 vector. Proteomics analysis was performed to screen its downstream targets. miR-1a-3p was the only miRNA showing interactive effects between maternal and offspring diets. It was upregulated in male offspring islets, further exacerbated by late-adulthood HFD re-exposure. Functionally, miR-1a-3p overexpression increased fasting glucose, impaired glucose and insulin tolerance, reduced ATP production and mitochondrial membrane potential, without affecting apoptosis. NBR1 was confirmed as a direct target of miR-1a-3p. NBR1 silencing mimicked miR-1a-3p's detrimental effects on β-cell mitochondria and function. Inhibition of miR-1a-3p alleviated HFD-induced β-cell dysfunction. miR-1a-3p mediates β-cell dysfunction programmed by early-life maternal HSF exposure through targeting NBR1 and disrupting mitochondrial function, representing a potential therapeutic strategy for preventing type 2 diabetes transmission.</p>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":" ","pages":"110480"},"PeriodicalIF":5.2,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148689568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Highly expressed ACSF2 contributes to butyrate utilization in the rumen epithelium.","authors":"Mingmei Song, Jing Qin, Junru Tian, Kai Zhang, Yali Zhang, Xiao'e Xiang, Weiyun Zhu, Shengyong Mao, Junhua Liu, Zan Huang","doi":"10.1016/j.jnutbio.2026.110479","DOIUrl":"https://doi.org/10.1016/j.jnutbio.2026.110479","url":null,"abstract":"<p><p>Ruminant epithelia preferentially catabolize butyrate to fuel metabolism, yet the mechanism by which the rumen epithelium establishes this preference remains unclear. Here, we identify ACSF2 as a mitochondrial acyl‑CoA synthetase (ACS) that catalyzes the activation of butyrate to butyryl‑CoA, thereby enabling rumen butyrate preference. We found that ACSF2 is markedly enriched in the forestomachs across ovine organs, with expression far exceeding other ACSs in the rumen epithelium, and it is rising during postnatal establishment of fermentative function. Single‑cell transcriptomics and immunostaining localize ACSF2 to the mitochondria‑rich layers, where it is co‑expressed in mitochondria with ketogenesis genes, notably the rate‑limiting enzyme HMGCS2. Further gain‑ and loss‑of‑function experiments show that ACSF2 activates butyrate to butyryl‑CoA, enhances butyrate‑supported growth, and is required for efficient butyrate consumption, cell fitness, and ketogenesis under butyrate‑dependent conditions. These findings define ACSF2 as a key mitochondrial gatekeeper for butyrate utilization in the rumen epithelium, providing a molecular mechanism for butyrate‑biased energy metabolism during rumen maturation.</p>","PeriodicalId":16618,"journal":{"name":"Journal of Nutritional Biochemistry","volume":" ","pages":"110479"},"PeriodicalIF":5.2,"publicationDate":"2026-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148664093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}