Molecular Metabolism最新文献

{"title":"Apolipoprotein E receptor 2 in endothelium promote glucose tolerance by mediating insulin delivery to skeletal muscle.","authors":"Anastasia Sacharidou, Ken L Chambliss, Jun Peng, Keiji Tanigaki, Md Nurul Islam, Shashank Sirsi, Andrew Lemoff, Kenneth Hoyt, Chieko Mineo, Philip W Shaul","doi":"10.1016/j.molmet.2025.102238","DOIUrl":"10.1016/j.molmet.2025.102238","url":null,"abstract":"<p><strong>Objective: </strong>The delivery of circulating insulin to skeletal muscle myocytes is a rate-limiting step in peripheral insulin action, and there is minimal understanding of the underlying mechanisms in endothelial cells. Recognizing that the LDL receptor family member apolipoprotein E receptor 2 (ApoER2, also known as LRP8) mediates apolipoprotein E (ApoE)-induced signaling in endothelial cells, the present project determined if endothelial ApoER2 influences glucose homeostasis in mice.</p><p><strong>Methods: </strong>Mice were generated deficient in ApoER2 selectively in endothelial cells, and glucose homeostasis was studied. Insulin-stimulated recruitment of the skeletal muscle microvasculature was assessed using contrast-enhanced ultrasound imaging. Endothelial cell insulin uptake and transcytosis were evaluated in culture. The ApoER2 interactome in endothelial cells was interrogated using immunoprecipitation and liquid chromatography/tandem mass spectrometry. ApoER2 structure-function was studied by mutagenesis.</p><p><strong>Results: </strong>Mice deficient in endothelial cell ApoER2 are glucose intolerant and insulin resistant due to a blunting of skeletal muscle glucose disposal that is related to a decrease in muscle insulin delivery. Endothelial ApoER2 manipulation does not alter direct insulin action on skeletal muscle or insulin-stimulated recruitment of the skeletal muscle microvasculature. Instead, ApoER2 stimulation by apolipoprotein E3 (ApoE3) increases endothelial cell insulin uptake and transcytosis. ApoE3 and ApoER2 stimulation of endothelial insulin transport require the ApoER2 adaptor protein Dab2 and the scaffolding protein IQGAP1, which is known to mediate insulin secretion by pancreatic β cells. IQGAP1 is not required for ApoE3/ApoER2-induced insulin uptake by endothelial cells; alternatively it is necessary for insulin transcytosis. ApoE3 prompts IQGAP1 recruitment to the exocyst complex, and ApoER2 interaction with IQGAP1 is necessary for the recruitment.</p><p><strong>Conclusions: </strong>In endothelial cells the ApoE3 and ApoER2 tandem co-opts the role of IQGAP1 in pancreatic β cells insulin secretion to enhance endothelial insulin transport. In this manner endothelial ApoER2 promotes glucose disposal in skeletal muscle and supports normal glucose homeostasis.</p>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102238"},"PeriodicalIF":6.6,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145000984","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":"Dual leucine zipper-bearing kinase DLK is necessary for cell autonomous regulation of insulin sensitivity","authors":"Hetty N. Wong ,&nbsp;Nathan Qi ,&nbsp;Edward B. Arias ,&nbsp;Kae Won Cho ,&nbsp;Deepak Nihalani ,&nbsp;Gregory D. Cartee ,&nbsp;Lawrence B. Holzman","doi":"10.1016/j.molmet.2025.102244","DOIUrl":"10.1016/j.molmet.2025.102244","url":null,"abstract":"<div><div>Metabolic syndrome and insulin resistance are driven in part by dysregulated signaling through the c-Jun N-terminal kinase (JNK) pathway. The scaffold protein JIP1 and its upstream kinase DLK (dual leucine zipper kinase) form a dynamic signaling complex that modulates JNK activity, yet the physiological role of DLK in glucose metabolism remains undefined. Here, we identify DLK as a critical regulator of insulin sensitivity using three genetically modified mouse models: a hypomorphic DLK allele, a tamoxifen-inducible whole-body DLK knockout, and a high-fat diet–induced obese model with DLK ablation. All models exhibited enhanced insulin sensitivity independent of adiposity, characterized by increased glucose uptake in muscle and adipose tissue, and improved suppression of hepatic glucose production during hyperinsulinemic-euglycemic clamp studies. Mechanistically, we demonstrate that DLK functions in a cell-autonomous manner, limiting insulin signaling through modulation of AKT and IRS1 phosphorylation downstream of insulin stimulation. In cultured myoblasts and fibroblasts, DLK was required for JNK activation and subsequent dampening of insulin signaling. These findings establish DLK as a regulator of whole-body insulin sensitivity, independent of obesity through a JIP-JNK signaling module. The results suggest that targeting DLK could represent a therapeutic strategy for improving insulin sensitivity in metabolic disease.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102244"},"PeriodicalIF":6.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144993012","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":"Corrigendum to 'Systemic metabolic changes in acute and chronic lymphocytic choriomeningitis virus infection' [Mol Metab Volume 99 (2025) Article 102194].","authors":"Caroline R Bartman, Shengqi Hou, Fabian Correa, Yihui Shen, Victoria da Silva-Diz, Maya Aleksandrova, Daniel Herranz, Joshua D Rabinowitz, Andrew M Intlekofer","doi":"10.1016/j.molmet.2025.102217","DOIUrl":"10.1016/j.molmet.2025.102217","url":null,"abstract":"","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":" ","pages":"102217"},"PeriodicalIF":6.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144765091","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":"Constructing chimeric mouse islets to study alpha- and delta-cell influence on beta-cell feature","authors":"Alexis Fouque ,&nbsp;Masaya Oshima ,&nbsp;Nina Mode ,&nbsp;Romain Ducellier ,&nbsp;Delphine Thibaut ,&nbsp;Florence Gbahou ,&nbsp;Latif Rachdi ,&nbsp;Over Cabrera ,&nbsp;Raphaël Scharfmann","doi":"10.1016/j.molmet.2025.102245","DOIUrl":"10.1016/j.molmet.2025.102245","url":null,"abstract":"<div><h3>Objectives</h3><div>This study aimed to evaluate the role of alpha- and delta-cell signals on beta-cells within pancreatic mouse islets. Specifically, we investigated how these signals regulate glucose sensitivity, gene expression and function in beta-cells.</div></div><div><h3>Methods</h3><div>We first implemented our previous protocol to FACS purify alpha-, beta-, and delta-cells by adding CD81 as a positive marker for alpha-cells. We next developed an approach to reaggregate these sorted cell populations, creating chimeric islets with different proportions of each endocrine cell type. We used these chimeric islets to study the effect of alpha- and delta-cells on glucose sensitivity, gene expression and function in beta-cells.</div></div><div><h3>Results</h3><div>We generated chimeric islets containing either all three endocrine cell types, alpha- + beta-cells or only beta-cells. We demonstrate that beta-cell glucose sensitivity and identity are independent of signals from alpha- and delta-cells. We identified a subset of genes including Pro-dynorphin, Fumarate hydratase and Txnip whose expression in beta-cells depends on alpha-cells signals acting through the glucagon- and glucagon-like peptide receptors. Finally, we demonstrated that in mouse beta-cell, KCl-mediated insulin secretion relies on an activation of the glucagon-receptor, while glucose-stimulated insulin secretion depends on glucagon-like peptide receptor activation.</div></div><div><h3>Conclusions</h3><div>We developed an innovative and easy-to-use model to reconstruct chimeric islets containing different frequencies of alpha-, beta- and delta-cells. Through this approach, we provide new insights into the complex regulatory mechanisms governing the role of alpha and delta cells on beta-cell features within islets.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102245"},"PeriodicalIF":6.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144993046","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":"Corrigendum to “Kynurenic acid derived from mesentery regulates mesenteritis and colitis via inducing white adipose browning in Crohn's disease” [Mol Metab 99 (2025 Sep) 102203]","authors":"Yongheng Wang ,&nbsp;Ritian Lin ,&nbsp;Fangtao Wang ,&nbsp;Huijun Fu ,&nbsp;Xia Wang ,&nbsp;Fengshan Jin ,&nbsp;Qiao Wang ,&nbsp;Weigang Shu","doi":"10.1016/j.molmet.2025.102240","DOIUrl":"10.1016/j.molmet.2025.102240","url":null,"abstract":"","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"100 ","pages":"Article 102240"},"PeriodicalIF":6.6,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144917002","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":"DYRK1A inhibition restores pancreatic functions and improves glucose metabolism in a preclinical model of type 2 diabetes","authors":"Romane Bertrand ,&nbsp;Stefania Tolu ,&nbsp;Delphine Picot ,&nbsp;Cécile Tourrel-Cuzin ,&nbsp;Ayoub Ouahab ,&nbsp;Julien Dairou ,&nbsp;Emmanuel Deau ,&nbsp;Mattias F. Lindberg ,&nbsp;Laurent Meijer ,&nbsp;Jamileh Movassat ,&nbsp;Benjamin Uzan","doi":"10.1016/j.molmet.2025.102242","DOIUrl":"10.1016/j.molmet.2025.102242","url":null,"abstract":"<div><h3>Objectives</h3><div>Insulin deficiency caused by the loss of β cells and/or impaired insulin secretion is a key factor in the pathogenesis of type 2 diabetes (T2D). The restoration of β cell number and function is thus a promising strategy to combat diabetes. Dual-specificity tyrosine-regulated kinase 1A (DYRK1A) has been shown to regulate human β cell proliferation. DYRK1A inhibitors are potential therapeutic tools, due to their ability to induce β cell proliferation. However, their anti-diabetic effects in the complex setting of type 2 diabetes remains unexplored. The aim of this study was to determine the impact of chronic DYRK1A inhibition on the remission of diabetes in pre-diabetic and overtly diabetic Goto-Kakizaki (GK) rats.</div></div><div><h3>Methods</h3><div>We assessed the impact of <em>in vivo</em> treatment with a DYRK1A inhibitor, Leucettinib-92, on β cell proliferation and insulin secretion in GK rats. Further, we evaluated the effects of long-term Leucettinib-92 treatment on the whole-body glucose metabolism in overtly diabetic GK rats through the assessment of fasting and post-absorptive glycemia, glucose tolerance and insulin sensitivity.</div></div><div><h3>Results</h3><div>Short-term <em>in vivo</em> treatment of prediabetic GK rats with Leucettinb-92 stimulated β cell proliferation <em>in vivo</em>, and sustainably prevented the development of overt hyperglycemia. Long-term treatment of adult GK rats with established diabetes increased the β cell mass and reduced basal hyperglycemia. Leucettinib-92 treatment also improved glucose tolerance, and glucose-induced insulin secretion <em>in vivo</em>.</div></div><div><h3>Conclusions</h3><div>We show that DYRK1A inhibition restores the β cell mass and function in a preclinical model of T2D, leading to the improvement of body's global glucose homeostasis.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102242"},"PeriodicalIF":6.6,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961608","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":"Suppression of adipocyte ABHD6 favors anti-inflammatory and adipogenic programs to preserve adipose tissue fitness in obesity","authors":"Pegah Poursharifi ,&nbsp;Camille Attané ,&nbsp;Isabelle Chenier ,&nbsp;Clemence Schmitt ,&nbsp;Roxane Lussier ,&nbsp;Anfal Al-Mass ,&nbsp;Yat Hei Leung ,&nbsp;Abel Oppong ,&nbsp;Élizabeth Dumais ,&nbsp;Nicolas Flamand ,&nbsp;Mohamed Abu-Farha ,&nbsp;Jehad Abubaker ,&nbsp;Fahd Al-Mulla ,&nbsp;Ying Bai ,&nbsp;Dongwei Zhang ,&nbsp;Marie-Line Peyot ,&nbsp;André Tchernof ,&nbsp;S.R. Murthy Madiraju ,&nbsp;Marc Prentki","doi":"10.1016/j.molmet.2025.102241","DOIUrl":"10.1016/j.molmet.2025.102241","url":null,"abstract":"<div><div>Some individuals exhibit metabolically healthy obesity, characterized by the expansion of white adipose tissue (WAT) without associated complications. The monoacylglycerol (MAG) hydrolase α/β-hydrolase domain-containing 6 (ABHD6) has been implicated in energy metabolism, with its global deletion conferring protection against obesity. However, the immunometabolic roles of adipocyte ABHD6 in WAT remodeling in response to nutri-stress and obesity are not known. Here, we demonstrate that in insulin resistant women, <em>ABHD6</em> mRNA expression is elevated in visceral fat and positively correlates with obesity and metabolic dysregulation. ABHD6 expression is also elevated in the WATs of diet-induced obese and <em>db/db</em> mice. Although adipocyte-specific ABHD6 knockout (AA-KO) mice become obese under high-fat diet, they show higher plasma adiponectin, reduced circulating insulin and inflammatory markers, improved insulin sensitivity, and lower plasma and liver triglycerides. They also show enhanced insulin action in various tissues, but normal glucose tolerance. In addition, AA-KO mice display healthier and less inflamed expansion of visceral fat, with smaller adipocytes and higher stimulated lipolysis and fatty acid oxidation levels. Similar but less prominent phenotype was found in the subcutaneous and brown fat depots. Thus, adipocyte ABHD6 suppression prevents most of the metabolic and inflammatory complications of obesity, but not obesity <em>per se</em>. Mechanistically, this beneficial process involves a rise in MAG levels in mature adipocytes, and their secretion, resulting in a crosstalk among adipocytes, preadipocytes and macrophages in the adipose microenvironment. Elevated intracellular MAG causes PPARs activation in adipocytes, and MAG secreted from adipocytes curtails the inflammatory polarization of macrophages and promotes preadipocyte differentiation. Hence, adipocyte ABHD6 and MAG hydrolysis contribute to unhealthy WAT remodeling and expansion in obesity, and its suppression represents a candidate strategy to uncouple obesity from many of its immunometabolic complications.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102241"},"PeriodicalIF":6.6,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961659","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":"KAT6A acetylation regulates AMPK function and hypertrophic remodeling in the heart","authors":"Mariko Aoyagi Keller ,&nbsp;Andreas Ivessa ,&nbsp;Tong Liu ,&nbsp;Hong Li ,&nbsp;Peter J. Romanienko ,&nbsp;Michinari Nakamura","doi":"10.1016/j.molmet.2025.102239","DOIUrl":"10.1016/j.molmet.2025.102239","url":null,"abstract":"<div><div>Diets influence metabolism and disease susceptibility, with lysine acetyltransferases (KATs) serving as key regulators through acetyl-CoA. We have previously demonstrated that a ketogenic diet alleviates cardiac pathology, though the underlying mechanisms remain largely unknown. Here we show that KAT6A acetylation is crucial for mitochondrial function and cell growth. Proteomic analysis revealed that KAT6A is acetylated at lysine (K)816 in the hearts of mice fed a ketogenic diet under hypertension, which enhances its interaction with AMPK regulatory subunits. RNA-sequencing analysis demonstrated that the KAT6A acetylation-mimetic mutant stimulates AMPK signaling in cardiomyocytes. Moreover, the acetylation-mimetic mutant mitigated phenylephrine-induced mitochondrial dysfunction and cardiomyocyte hypertrophy via AMPK activation. However, KAT6A-K816R acetylation-resistant knock-in mice unexpectedly exhibited smaller hearts with enhanced AMPK activity, conferring protection against neurohumoral stress-induced cardiac hypertrophy and remodeling. These findings indicate that KAT6A regulates metabolism and cellular growth by interacting with and modulating AMPK activity through K816-acetylation in a cell type-specific manner.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"101 ","pages":"Article 102239"},"PeriodicalIF":6.6,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961656","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":"Placental mitochondrial calcium uniporter modulates offspring susceptibility to metabolic dysfunction","authors":"Seokwon Jo ,&nbsp;Grace Chung ,&nbsp;Yu-Jin Youn ,&nbsp;Charlotte Hunt ,&nbsp;Ava Hill ,&nbsp;Megan Beetch ,&nbsp;Brian Akhaphong ,&nbsp;Elizabeth A. Morgan ,&nbsp;Perrie F. O'Tierney-Ginn ,&nbsp;Sarah A. Wernimont ,&nbsp;Emilyn U. Alejandro","doi":"10.1016/j.molmet.2025.102236","DOIUrl":"10.1016/j.molmet.2025.102236","url":null,"abstract":"<div><div>Mitochondria are crucial for regulating metabolism, but their role in the placenta and how they may shape offspring metabolism and long-term health remains unclear, despite being commonly associated with pregnancy complications. To investigate this, we used a genetic model with placenta-specific deletion of the mitochondrial calcium uniporter (Pl-MCUKO) and assessed the metabolic trajectory of adult offspring. We found that, at baseline, female placental trophoblasts in wild-type animals exhibited higher respiration rates than males. MCU deletion impaired mitochondrial function specifically in female placentas and was accompanied by distinct changes in the metabolomic profiles of protein and lipid metabolism. Transcriptome analysis revealed reduced placental cellular growth pathways, consistent with smaller placentas and reduced embryonic body weights in Pl-MCUKO. Although <em>in utero</em> MCU deletion affected fetal growth, it was insufficient to cause permanent postnatal changes in body weight, as these deficits normalized in adulthood, with normal glucose homeostasis in Pl-MCUKO offspring. However, when challenged with a high-fat diet, Pl-MCUKO females exhibited reduced weight gain, improved glucose and insulin tolerance, smaller fat depots, and increased ambulatory activity compared to controls. This improved metabolic profile was associated with reduced pancreatic β-cell mass but preserved β-cell function. These findings provide direct evidence that placental mitochondrial function can influence the long-term metabolic health of female offspring by modulating key metabolic tissues.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"100 ","pages":"Article 102236"},"PeriodicalIF":6.6,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144925111","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":"ACAA1 knockout increases the survival rate of KPC mice by activating autophagy","authors":"Ho Lee ,&nbsp;Mingyu Kang ,&nbsp;Sung Hoon Sim ,&nbsp;Joon Hee Kang ,&nbsp;Wonyoung Choi ,&nbsp;Jung Won Chun ,&nbsp;Woosol Hong ,&nbsp;Chaeyoung Kim ,&nbsp;Woojin Ham ,&nbsp;Jeong Hwan Park ,&nbsp;Eun-Byeol Koh ,&nbsp;Yoon Jeon ,&nbsp;Sang Myung Woo ,&nbsp;Soo-Youl Kim","doi":"10.1016/j.molmet.2025.102237","DOIUrl":"10.1016/j.molmet.2025.102237","url":null,"abstract":"<div><h3>Objectives</h3><div>We found that the levels of the peroxisomal fatty acid oxidation (FAO) marker in pancreatic ductal adenocarcinoma (PDAC) patients were higher than those in healthy individuals, based on tissue microarray analysis. This study investigates FAO in preclinical in vitro and in vivo models.</div></div><div><h3>Methods</h3><div>To examine the role of FAO in the peroxisome, we created acetyl-coenzyme A acyltransferase (ACAA1) knockout mice, crossed them with KPC mice, and monitored their survival rates. Additionally, we tested a mouse xenograft model with ACAA1 knockdown in human PDAC cells.</div></div><div><h3>Results</h3><div>In normal cells, <em>ACAA1</em> knockdown did not affect oxygen consumption. In contrast, in PDAC cells, <em>ACAA1</em> knockdown reduced the oxygen consumption rate by up to 60% and decreased ATP production by up to 70%. This suggests that peroxisomes in PDAC supply various acyl-carnitines for FAO in mitochondria. In PDAC cells, <em>ACAA1</em> knockdown lowered ATP levels, resulting in mTOR inactivation and autophagy induction. Additionally, <em>ACAA1</em> knockdown significantly increased LC3-II levels, leading to growth retardation in mouse xenograft models. <em>Acaa1a</em>^{<em>+/−</em>} mice showed a median survival increase of 3 weeks after crossing <em>Acaa1a</em>^{<em>+/−</em>} with KPC mice (<em>Kras</em>^G12D/+; <em>Trp53</em>^R172H/+; <em>Pdx1</em>-Cre, a genetically engineered mice model for PDAC).</div></div><div><h3>Conclusions</h3><div><em>ACAA1</em> knockdown inhibited tumor growth by triggering autophagy, which supported the survival of KPC mice. The most important benefit of targeting ACAA1 is that it blocks tumor growth specifically in cancer cells without harming normal cell energy metabolism.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"100 ","pages":"Article 102237"},"PeriodicalIF":6.6,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144916998","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}