Pub Date : 2025-12-29DOI: 10.1016/j.metabol.2025.156486
De-Hua Liao , Shi-Long Jiang , Ting Wu , Zeng Cao , Ze-Wu Zhu , Nayiyuan Wu , Xiu Zhang , Ming-Hui Long , Jing Wang , Zhi-Bin Wang
Transient receptor potential (TRP) channels are not only multimodal ion sensors but also couplers between metabolic states and immune responses. TRP gating is controlled by lipid signaling (PIP2, DAG, cholesterol), redox/energy cues (NAD+/ADPR/ROS, ATP/AMP), and metabolite-derived signals (pH/lactate, bile acids, endocannabinoids, eicosanoids, SCFAs). In turn, TRP-driven Ca2+ signaling reprograms AMPK–mTORC1, glycolysis/OXPHOS, FAO, and glutaminolysis, thereby reshaping the metabolic programs and effector functions of T/B cells, macrophages, NK/DCs. In gut, skin, and arthritis, microbiota–metabolite–TRP axes dictate inflammatory phenotypes; within tumors, lactate, adenosine, and kynurenine modulate TRPs in cancer and immune infiltrates. In this study, we synthesize TRP metabolic sensing mechanisms, immunometabolic reprogramming, and pharmacological opportunities, highlighting synergistic strategies combining metabolic interventions with TRP modulation for precision management of inflammation-related diseases.
{"title":"TRP channels at the crossroads of metabolism and immunity: ion–metabolite coupling in inflammation and disease","authors":"De-Hua Liao , Shi-Long Jiang , Ting Wu , Zeng Cao , Ze-Wu Zhu , Nayiyuan Wu , Xiu Zhang , Ming-Hui Long , Jing Wang , Zhi-Bin Wang","doi":"10.1016/j.metabol.2025.156486","DOIUrl":"10.1016/j.metabol.2025.156486","url":null,"abstract":"<div><div>Transient receptor potential (TRP) channels are not only multimodal ion sensors but also couplers between metabolic states and immune responses. TRP gating is controlled by lipid signaling (PIP2, DAG, cholesterol), redox/energy cues (NAD<sup>+</sup>/ADPR/ROS, ATP/AMP), and metabolite-derived signals (pH/lactate, bile acids, endocannabinoids, eicosanoids, SCFAs). In turn, TRP-driven Ca<sup>2+</sup> signaling reprograms AMPK–mTORC1, glycolysis/OXPHOS, FAO, and glutaminolysis, thereby reshaping the metabolic programs and effector functions of T/B cells, macrophages, NK/DCs. In gut, skin, and arthritis, microbiota–metabolite–TRP axes dictate inflammatory phenotypes; within tumors, lactate, adenosine, and kynurenine modulate TRPs in cancer and immune infiltrates. In this study, we synthesize TRP metabolic sensing mechanisms, immunometabolic reprogramming, and pharmacological opportunities, highlighting synergistic strategies combining metabolic interventions with TRP modulation for precision management of inflammation-related diseases.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"176 ","pages":"Article 156486"},"PeriodicalIF":11.9,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145878710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-29DOI: 10.1016/j.metabol.2025.156487
Bo Chen , Yuan-yuan Ma , Miao-qing Zhang , Rui Zhang , Shu-fen Li , Lin-zhuan Wu , Jing-pu Zhang
Targeting autophagy and fatty acid metabolism may be two promising therapeutic strategies for treating metabolic dysfunction-associated steatotic liver disease (MASLD). Our previous research demonstrated the ability of isarubrolone C (IroC), a bioactive polycyclic tropoloalkaloid to induce autophagy. However, the effects and mechanisms of IroC on MASLD have yet to be explored. Here, we generated a steatosis cell model using a minimum essential medium containing oleic acid and palmitic acid (HFA) in HepG2 cells, and a zebrafish model of hepatic steatosis fed a high-fat diet (HFD), and explored the role and mechanism of IroC against hepatic steatosis. HFA and HFD exposure caused lipid accumulation, fatty acid oxidation (FAO) defect and high expression of lipogenesis genes, and IroC treatment reversed these steatosis-like features in vitro and in the liver of zebrafish with MASLD. Mechanistically, IroC increased AMPK phosphorylation that further phosphorylated ULK1, ACC, PPARα and full-length SREBP1, by which lipophagy and FAO damaged by HFA were recovered, expression of de novo lipogenesis genes reduced, including fasn and scd1 expression via downregulation of SREBP-1 activity; and CD36 for FA transport was decreased by p-AMPK inhibition of PPARγ phosphorylation. Notably, IroC exhibited a high binding affinity to the AMPKα1β2γ1 isoform, as demonstrated by both molecular docking and surface plasmon resonance assay. Our work uncovers that IroC exerts an activator of AMPK, by which IroC can activate lipophagy and FAO, and inhibit lipogenesis and lipid deposition in hepatocytes. Thereby, IroC has the potential to serve as an effective agent in the management of MASLD.
{"title":"Suppression of hepatosteatosis by isarubrolone C through AMPK-dependent regulation of lipophagy and lipid metabolism","authors":"Bo Chen , Yuan-yuan Ma , Miao-qing Zhang , Rui Zhang , Shu-fen Li , Lin-zhuan Wu , Jing-pu Zhang","doi":"10.1016/j.metabol.2025.156487","DOIUrl":"10.1016/j.metabol.2025.156487","url":null,"abstract":"<div><div>Targeting autophagy and fatty acid metabolism may be two promising therapeutic strategies for treating metabolic dysfunction-associated steatotic liver disease (MASLD). Our previous research demonstrated the ability of isarubrolone C (IroC), a bioactive polycyclic tropoloalkaloid to induce autophagy. However, the effects and mechanisms of IroC on MASLD have yet to be explored. Here, we generated a steatosis cell model using a minimum essential medium containing oleic acid and palmitic acid (HFA) in HepG2 cells, and a zebrafish model of hepatic steatosis fed a high-fat diet (HFD), and explored the role and mechanism of IroC against hepatic steatosis. HFA and HFD exposure caused lipid accumulation, fatty acid oxidation (FAO) defect and high expression of lipogenesis genes, and IroC treatment reversed these steatosis-like features <em>in vitro</em> and in the liver of zebrafish with MASLD. Mechanistically, IroC increased AMPK phosphorylation that further phosphorylated ULK1, ACC, PPARα and full-length SREBP1, by which lipophagy and FAO damaged by HFA were recovered, expression of <em>de novo</em> lipogenesis genes reduced, including <em>fasn</em> and <em>scd1</em> expression <em>via</em> downregulation of SREBP-1 activity; and CD36 for FA transport was decreased by p-AMPK inhibition of PPARγ phosphorylation. Notably, IroC exhibited a high binding affinity to the AMPKα1β2γ1 isoform, as demonstrated by both molecular docking and surface plasmon resonance assay. Our work uncovers that IroC exerts an activator of AMPK, by which IroC can activate lipophagy and FAO, and inhibit lipogenesis and lipid deposition in hepatocytes. Thereby, IroC has the potential to serve as an effective agent in the management of MASLD.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"176 ","pages":"Article 156487"},"PeriodicalIF":11.9,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145878702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-23DOI: 10.1016/j.metabol.2025.156485
Gang Fan , Weiming Guo , Jingfen Lu , Yaohui He , Jinhui Zha , Qingping Zhang , Yuling Chen , Dong Tan , Zhihan Tang , Jing Yang , Zhijian Yu , Miao Liu
Background
Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of low-density lipoprotein receptors (LDLR), leading to elevated plasma LDL cholesterol (LDL-C) and increased risk of hypercholesterolemia. Current therapeutic approaches, such as monoclonal antibodies and gene-editing tools, face significant challenges including high cost, safety issues, and limited ability to target intracellular PCSK9.
Methods
Using computer-aided drug design (CADD), we developed Cadd4, a novel peptide-based degrader targeting PCSK9. Molecular docking was employed to identify a high-affinity peptide sequence, which was then validated through in vitro studies using LX-2 cells and in vivo experiments in high-fat diet (HFD)-induced hypercholesterolemic mice. Biodistribution and toxicity assessments were performed to evaluate tissue specificity and safety. Human liver tissue experiments were conducted to assess translational efficacy.
Results
Cadd4 exhibited efficient intracellular uptake and significantly reduced PCSK9 levels, resulting in upregulated LDLR expression. In HFD-fed mice, hepatic PCSK9 was decreased by 38 %, accompanied by a 25 % reduction in total cholesterol and a 29 % reduction in LDL-C. Biodistribution analysis revealed liver-specific accumulation with no signs of systemic toxicity. In human liver tissues, Cadd4 effectively degraded PCSK9 and restored LDLR expression. Compared with the clinical-stage PCSK9 inhibitor, Cadd4 demonstrated promising lipid-lowering efficacy and the potential for a longer duration of action.
Conclusion
Cadd4 represents a promising CADD-designed therapeutic strategy for cholesterol management by targeting intracellular PCSK9 for degradation. This approach overcomes key limitations of existing therapies and underscores the potential of targeted protein degradation in cardiovascular disease treatment.
{"title":"CADD-engineered peptide protacs efficiently target PCSK9 for hypercholesterolemia in vivo","authors":"Gang Fan , Weiming Guo , Jingfen Lu , Yaohui He , Jinhui Zha , Qingping Zhang , Yuling Chen , Dong Tan , Zhihan Tang , Jing Yang , Zhijian Yu , Miao Liu","doi":"10.1016/j.metabol.2025.156485","DOIUrl":"10.1016/j.metabol.2025.156485","url":null,"abstract":"<div><h3>Background</h3><div>Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of low-density lipoprotein receptors (LDLR), leading to elevated plasma LDL cholesterol (LDL-C) and increased risk of hypercholesterolemia. Current therapeutic approaches, such as monoclonal antibodies and gene-editing tools, face significant challenges including high cost, safety issues, and limited ability to target intracellular PCSK9.</div></div><div><h3>Methods</h3><div>Using computer-aided drug design (CADD), we developed Cadd4, a novel peptide-based degrader targeting PCSK9. Molecular docking was employed to identify a high-affinity peptide sequence, which was then validated through in vitro studies using LX-2 cells and in vivo experiments in high-fat diet (HFD)-induced hypercholesterolemic mice. Biodistribution and toxicity assessments were performed to evaluate tissue specificity and safety. Human liver tissue experiments were conducted to assess translational efficacy.</div></div><div><h3>Results</h3><div>Cadd4 exhibited efficient intracellular uptake and significantly reduced PCSK9 levels, resulting in upregulated LDLR expression. In HFD-fed mice, hepatic PCSK9 was decreased by 38 %, accompanied by a 25 % reduction in total cholesterol and a 29 % reduction in LDL-C. Biodistribution analysis revealed liver-specific accumulation with no signs of systemic toxicity. In human liver tissues, Cadd4 effectively degraded PCSK9 and restored LDLR expression. Compared with the clinical-stage PCSK9 inhibitor, Cadd4 demonstrated promising lipid-lowering efficacy and the potential for a longer duration of action.</div></div><div><h3>Conclusion</h3><div>Cadd4 represents a promising CADD-designed therapeutic strategy for cholesterol management by targeting intracellular PCSK9 for degradation. This approach overcomes key limitations of existing therapies and underscores the potential of targeted protein degradation in cardiovascular disease treatment.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"176 ","pages":"Article 156485"},"PeriodicalIF":11.9,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145834402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-21DOI: 10.1016/j.metabol.2025.156484
Andrea Giustina , Luigi di Filippo , Aneta Aleksova , Jens Bollerslev , Anna Maria Colao , Bess Dawson-Hughes , Lorenzo M. Donini , Peter R. Ebeling , Marise Lazaretti-Castro , Roberto Lorusso , Livio Luzi , Claudio Marcocci , Salvatore Minisola , Nicola Napoli , Anastassios G. Pittas , René Rizzoli , Patrizia Rovere Querini , Ferruccio Santini , Anne L. Schafer , Jyrki K. Virtanen , John P. Bilezikian
The 8th International Conference Controversies in Vitamin D, held in September 2024, convened leading experts to address the multifaceted role of vitamin D in human health. Key discussions focused on its influence on metabolic health, including effects on sarcopenia, muscle function, and energy metabolism, as well as its role in obesity, cardiovascular health, and diabetes. Preclinical evidence was presented, suggesting a pivotal role of vitamin D in regulating muscle function and repair, potentially preventing sarcopenia. A relationship between low vitamin D (25[OH]D) concentrations and increased risk of cardiovascular diseases and diabetes was supported by several preclinical and clinical studies. Vitamin D supplementation was recently demonstrated to help improve glycemia and reduce the progression to diabetes and increase the likelihood of regression to normal glucose regulation in adults with prediabetes. Despite mixed outcomes from large, population-based randomized clinical trials, the conference underscored the critical need for personalized research, through disease-specific clinical trials, to fully elucidate the therapeutic potential of vitamin D supplementation, particularly in chronic conditions such as cardiovascular diseases and diabetes. In conclusion, while vitamin D demonstrates considerable promise in modifying a wide array of metabolic health concerns, rigorous scientific inquiry is essential to deepen our understanding of its mechanisms as well as potential protective effects and establish evidence-based guidelines for supplementation. This growing body of work has the potential to significantly enhance clinical outcomes and improve public health strategies, calling for continued exploration and collaboration in the field of vitamin D research.
{"title":"Consensus statement on vitamin D role in metabolic health","authors":"Andrea Giustina , Luigi di Filippo , Aneta Aleksova , Jens Bollerslev , Anna Maria Colao , Bess Dawson-Hughes , Lorenzo M. Donini , Peter R. Ebeling , Marise Lazaretti-Castro , Roberto Lorusso , Livio Luzi , Claudio Marcocci , Salvatore Minisola , Nicola Napoli , Anastassios G. Pittas , René Rizzoli , Patrizia Rovere Querini , Ferruccio Santini , Anne L. Schafer , Jyrki K. Virtanen , John P. Bilezikian","doi":"10.1016/j.metabol.2025.156484","DOIUrl":"10.1016/j.metabol.2025.156484","url":null,"abstract":"<div><div>The 8th International Conference Controversies in Vitamin D, held in September 2024, convened leading experts to address the multifaceted role of vitamin D in human health. Key discussions focused on its influence on metabolic health, including effects on sarcopenia, muscle function, and energy metabolism, as well as its role in obesity, cardiovascular health, and diabetes. Preclinical evidence was presented, suggesting a pivotal role of vitamin D in regulating muscle function and repair, potentially preventing sarcopenia. A relationship between low vitamin D (25[OH]D) concentrations and increased risk of cardiovascular diseases and diabetes was supported by several preclinical and clinical studies. Vitamin D supplementation was recently demonstrated to help improve glycemia and reduce the progression to diabetes and increase the likelihood of regression to normal glucose regulation in adults with prediabetes. Despite mixed outcomes from large, population-based randomized clinical trials, the conference underscored the critical need for personalized research, through disease-specific clinical trials, to fully elucidate the therapeutic potential of vitamin D supplementation, particularly in chronic conditions such as cardiovascular diseases and diabetes. In conclusion, while vitamin D demonstrates considerable promise in modifying a wide array of metabolic health concerns, rigorous scientific inquiry is essential to deepen our understanding of its mechanisms as well as potential protective effects and establish evidence-based guidelines for supplementation. This growing body of work has the potential to significantly enhance clinical outcomes and improve public health strategies, calling for continued exploration and collaboration in the field of vitamin D research.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"176 ","pages":"Article 156484"},"PeriodicalIF":11.9,"publicationDate":"2025-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145820209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-20DOI: 10.1016/j.metabol.2025.156483
Xiaoxun Zhang , Jiaxin Lei , Nan Zhao , Zhixian Zhu , Jingjing Ding , Qiong Pan , Wen-Yue Liu , Xiao-Zhi Jin , Li-You Lian , Ming-Hua Zheng , Jin Chai
Background and aims
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common chronic liver condition that can result in significant liver damage. This study aimed to evaluate the effects of the SEMA7AN559Y mutation on MASLD progression and to explore potential therapeutic targets.
Methods
To examine the impact of the SEMA7AN559Y mutation on MASLD progression, we generated Sema7aN557Y (equal to human SEMA7AN559Y) heterozygous mutant mice. At 8 weeks old, both wild-type and Sema7aN557Y heterozygous mice were placed on a high-fat diet. After dietary intervention, mice were euthanized, and serum and liver tissues were collected for analysis. The effects of the SEMA7AN559Y mutation on MASLD progression were assessed using biochemical assays, histological analysis, and Western blotting.
Results
The Sema7aN557Y mutation worsened lipid metabolism disorders, causing hepatic steatosis, inflammation, and fibrosis in mice fed a high-fat diet. The SEMA7AN559Y mutation strengthens its interaction with integrin β1, triggering the PI3K/Akt pathway and increasing ROS production, which leads to hepatic oxidative stress and NLRP3 inflammasome activation.
Conclusion
The N559Y variant in SEMA7A suggests a potential association with exacerbated hepatic oxidative stress, heightened pyroptosis, and increased MASLD severity. Targeting the SEMA7A-integrin β1 interaction could represent a potential novel therapeutic approach.
{"title":"The SEMA7AN559Y mutation facilitates the development of metabolic dysfunction-associated steatotic liver disease by inducing ROS/NLRP3-mediated hepatic cell pyroptosis","authors":"Xiaoxun Zhang , Jiaxin Lei , Nan Zhao , Zhixian Zhu , Jingjing Ding , Qiong Pan , Wen-Yue Liu , Xiao-Zhi Jin , Li-You Lian , Ming-Hua Zheng , Jin Chai","doi":"10.1016/j.metabol.2025.156483","DOIUrl":"10.1016/j.metabol.2025.156483","url":null,"abstract":"<div><h3>Background and aims</h3><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common chronic liver condition that can result in significant liver damage. This study aimed to evaluate the effects of the <em>SEMA7A</em><sup>N559Y</sup> mutation on MASLD progression and to explore potential therapeutic targets.</div></div><div><h3>Methods</h3><div>To examine the impact of the <em>SEMA7A</em><sup>N559Y</sup> mutation on MASLD progression, we generated <em>Sema7a</em><sup>N557Y</sup> (equal to human <em>SEMA7A</em><sup>N559Y</sup>) heterozygous mutant mice. At 8 weeks old, both wild-type and <em>Sema7a</em><sup>N557Y</sup> heterozygous mice were placed on a high-fat diet. After dietary intervention, mice were euthanized, and serum and liver tissues were collected for analysis. The effects of the <em>SEMA7A</em><sup>N559Y</sup> mutation on MASLD progression were assessed using biochemical assays, histological analysis, and Western blotting.</div></div><div><h3>Results</h3><div>The <em>Sema7a</em><sup>N557Y</sup> mutation worsened lipid metabolism disorders, causing hepatic steatosis, inflammation, and fibrosis in mice fed a high-fat diet. The <em>SEMA7A</em><sup>N559Y</sup> mutation strengthens its interaction with integrin β1, triggering the PI3K/Akt pathway and increasing ROS production, which leads to hepatic oxidative stress and NLRP3 inflammasome activation.</div></div><div><h3>Conclusion</h3><div>The N559Y variant in SEMA7A suggests a potential association with exacerbated hepatic oxidative stress, heightened pyroptosis, and increased MASLD severity. Targeting the SEMA7A-integrin β1 interaction could represent a potential novel therapeutic approach.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"176 ","pages":"Article 156483"},"PeriodicalIF":11.9,"publicationDate":"2025-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145810603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-18DOI: 10.1016/j.metabol.2025.156470
Ziqi Yu , Lifeng Zhang , Bo Jiang , Lu Zhang , Minghui Chen , Mei Song
Fatty acids (FAs) are indispensable for cellular homeostasis and centered in anabolic and catabolic pathways that are tightly governed by long-chain acyl-CoA synthetases (ACSLs). These enzymes drive fatty acid β-oxidation (FAO) to generate energy, remodel cell membrane phospholipid composition to dictate ferroptosis susceptibility, coordinate steroidogenesis and eicosanoid biosynthesis, and mediate metabolic reprogramming, thus acting as a central nexus between FAs metabolism and cell death. Dysregulation of ACSLs across malignancies fosters oncogenic dependency on metabolic reprogramming, influencing tumor progression, immune modulation, and therapy resistance, offering a rationale for anticancer therapeutic opportunities. Here, we delineate the decisive roles of ACSLs in the metabolic fate of FAs and cell death execution. We dissect their tumorigenic mechanisms through metabolic rewiring and cell death modulation, with an emphasis on ACSLs-mediated crosstalk between ferroptosis and cancer immunity. Furthermore, we discuss the potential of ACSLs-targeted agents in tumor therapy and the treatment of ferroptosis-associated pathologies, offering actionable insights for clinical translation.
{"title":"The ACSL family: Bridging fatty acid metabolism and cell death in cancer progression","authors":"Ziqi Yu , Lifeng Zhang , Bo Jiang , Lu Zhang , Minghui Chen , Mei Song","doi":"10.1016/j.metabol.2025.156470","DOIUrl":"10.1016/j.metabol.2025.156470","url":null,"abstract":"<div><div>Fatty acids (FAs) are indispensable for cellular homeostasis and centered in anabolic and catabolic pathways that are tightly governed by long-chain acyl-CoA synthetases (ACSLs). These enzymes drive fatty acid β-oxidation (FAO) to generate energy, remodel cell membrane phospholipid composition to dictate ferroptosis susceptibility, coordinate steroidogenesis and eicosanoid biosynthesis, and mediate metabolic reprogramming, thus acting as a central nexus between FAs metabolism and cell death. Dysregulation of ACSLs across malignancies fosters oncogenic dependency on metabolic reprogramming, influencing tumor progression, immune modulation, and therapy resistance, offering a rationale for anticancer therapeutic opportunities. Here, we delineate the decisive roles of ACSLs in the metabolic fate of FAs and cell death execution. We dissect their tumorigenic mechanisms through metabolic rewiring and cell death modulation, with an emphasis on ACSLs-mediated crosstalk between ferroptosis and cancer immunity. Furthermore, we discuss the potential of ACSLs-targeted agents in tumor therapy and the treatment of ferroptosis-associated pathologies, offering actionable insights for clinical translation.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"176 ","pages":"Article 156470"},"PeriodicalIF":11.9,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145800562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-17DOI: 10.1016/j.metabol.2025.156469
Dong-Ho Kim , Mi Kyung Kim , Daehoon Kim , Eun-Jun Kwon , Jieun Shin , Sebin Lee , Bae-Gon Kang , Jae Won Yun , Jaebon Lee , Hye Won Lee , Byoung Kuk Jang , Ghilsuk Yoon , Kwang-Hyeon Liu , Jun-Kyu Byun , Yeon-Kyung Choi , Keun-Gyu Park
<div><h3>Background</h3><div>Immune checkpoint blockade (ICB) has revolutionized treatment of hepatocellular carcinoma (HCC), but its efficacy remains limited. Recent studies demonstrate that resistance to ferroptosis is a significant barrier to the success of ICB.</div></div><div><h3>Methods</h3><div>Ferroptosis was assessed by measuring C11-BODIPY fluorescence and 4-hydroxynonenal (4-HNE) staining. Epigenetic regulation of hepcidin under fatty acid-rich conditions in HCC cells was investigated through chromatin immunoprecipitation and histone methylation analyses. Clinical relevance was evaluated using ICB response datasets and analyses of tumor tissues from HCC patients.</div></div><div><h3>Results</h3><div>We demonstrate that prolonged exposure to high palmitate concentrations induces ferroptosis resistance in HCC cells by altering glutamine availability. Mechanistically, chronic exposure to palmitate and high-fat diet-feeding reduced glutamine-derived α-KG concentrations in HCC cells, leading to a H3K27me3-mediated reduction in <strong>hepcidin</strong> and depletion of the intracellular labile iron pool, thereby promoting resistance to anti-programmed death-ligand 1 (anti-PD-L1)-induced ferroptosis. This resistance was reversed by the EZH2 inhibitor tazemetostat, which epigenetically restored hepcidin expression in both <em>in vitro</em> and <em>in vivo</em> models. Notably, tumor tissues from HCC patients exhibited high FFA levels, along with low levels of glutamine, <strong>hepcidin,</strong> and iron, which correlated with shorter overall survival. H3K27me3-mediated suppression of hepcidin was further confirmed in patient cohorts.</div></div><div><h3>Conclusion</h3><div>Our study uncovers a previously unrecognized type of palmitate-induced metabolic reprogramming that confers resistance to ICB-induced ferroptosis on HCC, and propose a therapeutic strategy to overcome ferroptosis resistance under free fatty acid-rich conditions.</div></div><div><h3>Abbreviations</h3><div><span><div><div><table><tbody><tr><td>ICB</td><td>Immune checkpoint blockade</td></tr><tr><td>xCT</td><td>cystine/glutamate antiporter</td></tr><tr><td>CoQ10</td><td>coenzyme Q10</td></tr><tr><td>FSP1</td><td>ferroptosis suppressor protein 1</td></tr><tr><td>NADPH</td><td>nicotinamide adenine dinucleotide phosphate, reduced form</td></tr><tr><td>GSH</td><td>glutathione</td></tr><tr><td>GSSG</td><td>glutathione disulfide</td></tr><tr><td>HCC</td><td>hepatocellular carcinoma</td></tr><tr><td>AD</td><td>palmitate-adapted HCC cells</td></tr><tr><td>PI</td><td>propidium iodide</td></tr><tr><td>ROS</td><td>lipid reactive oxygen species</td></tr><tr><td>IKE</td><td>imidazole ketone erastin</td></tr><tr><td>GPX4</td><td>glutathione peroxidase-4</td></tr><tr><td>LIP</td><td>labile iron pool</td></tr><tr><td>SLC</td><td>solute carrier</td></tr><tr><td>NRF2</td><td>nuclear factor erythroid 2-related factor 2</td></tr><tr><td>FFA</td><td>free fatty acid</td></tr><tr><td>LFD</td><td>l
{"title":"Liver cancer chronically exposed to palmitate acquires ferroptosis resistance via the downregulation of glutamine-driven hepcidin expression","authors":"Dong-Ho Kim , Mi Kyung Kim , Daehoon Kim , Eun-Jun Kwon , Jieun Shin , Sebin Lee , Bae-Gon Kang , Jae Won Yun , Jaebon Lee , Hye Won Lee , Byoung Kuk Jang , Ghilsuk Yoon , Kwang-Hyeon Liu , Jun-Kyu Byun , Yeon-Kyung Choi , Keun-Gyu Park","doi":"10.1016/j.metabol.2025.156469","DOIUrl":"10.1016/j.metabol.2025.156469","url":null,"abstract":"<div><h3>Background</h3><div>Immune checkpoint blockade (ICB) has revolutionized treatment of hepatocellular carcinoma (HCC), but its efficacy remains limited. Recent studies demonstrate that resistance to ferroptosis is a significant barrier to the success of ICB.</div></div><div><h3>Methods</h3><div>Ferroptosis was assessed by measuring C11-BODIPY fluorescence and 4-hydroxynonenal (4-HNE) staining. Epigenetic regulation of hepcidin under fatty acid-rich conditions in HCC cells was investigated through chromatin immunoprecipitation and histone methylation analyses. Clinical relevance was evaluated using ICB response datasets and analyses of tumor tissues from HCC patients.</div></div><div><h3>Results</h3><div>We demonstrate that prolonged exposure to high palmitate concentrations induces ferroptosis resistance in HCC cells by altering glutamine availability. Mechanistically, chronic exposure to palmitate and high-fat diet-feeding reduced glutamine-derived α-KG concentrations in HCC cells, leading to a H3K27me3-mediated reduction in <strong>hepcidin</strong> and depletion of the intracellular labile iron pool, thereby promoting resistance to anti-programmed death-ligand 1 (anti-PD-L1)-induced ferroptosis. This resistance was reversed by the EZH2 inhibitor tazemetostat, which epigenetically restored hepcidin expression in both <em>in vitro</em> and <em>in vivo</em> models. Notably, tumor tissues from HCC patients exhibited high FFA levels, along with low levels of glutamine, <strong>hepcidin,</strong> and iron, which correlated with shorter overall survival. H3K27me3-mediated suppression of hepcidin was further confirmed in patient cohorts.</div></div><div><h3>Conclusion</h3><div>Our study uncovers a previously unrecognized type of palmitate-induced metabolic reprogramming that confers resistance to ICB-induced ferroptosis on HCC, and propose a therapeutic strategy to overcome ferroptosis resistance under free fatty acid-rich conditions.</div></div><div><h3>Abbreviations</h3><div><span><div><div><table><tbody><tr><td>ICB</td><td>Immune checkpoint blockade</td></tr><tr><td>xCT</td><td>cystine/glutamate antiporter</td></tr><tr><td>CoQ10</td><td>coenzyme Q10</td></tr><tr><td>FSP1</td><td>ferroptosis suppressor protein 1</td></tr><tr><td>NADPH</td><td>nicotinamide adenine dinucleotide phosphate, reduced form</td></tr><tr><td>GSH</td><td>glutathione</td></tr><tr><td>GSSG</td><td>glutathione disulfide</td></tr><tr><td>HCC</td><td>hepatocellular carcinoma</td></tr><tr><td>AD</td><td>palmitate-adapted HCC cells</td></tr><tr><td>PI</td><td>propidium iodide</td></tr><tr><td>ROS</td><td>lipid reactive oxygen species</td></tr><tr><td>IKE</td><td>imidazole ketone erastin</td></tr><tr><td>GPX4</td><td>glutathione peroxidase-4</td></tr><tr><td>LIP</td><td>labile iron pool</td></tr><tr><td>SLC</td><td>solute carrier</td></tr><tr><td>NRF2</td><td>nuclear factor erythroid 2-related factor 2</td></tr><tr><td>FFA</td><td>free fatty acid</td></tr><tr><td>LFD</td><td>l","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"176 ","pages":"Article 156469"},"PeriodicalIF":11.9,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145794302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-17DOI: 10.1016/j.metabol.2025.156471
Francesca D'Addio , Loredana Bucciarelli , Maria Elena Lunati , Paolo Fiorina
A growing body of evidence suggests that neurogenerative disorders are increasingly common in individuals with type 1 diabetes (T1D) and should be considered part of the heterogeneous impairment of the nervous system linked to the T1D condition. The already established association between brain health and blood glucose metabolic control pushes to normalize glycemia in individuals with neurodegenerative diseases as well as in those with T1D. Normoglycemia has, indeed, been associated with reduced brain atrophy and preserved neuronal plasticity and function. Interestingly, immune dysregulation recently demonstrated in neurodegenerative diseases may be highly relevant given the autoimmune nature of T1D. Poor glycemic control and a disrupted immune response may act as common pathogenic mechanisms that increase the incidence of neurodegenerative disorders in individuals with T1D and may unveil new diagnostic and therapeutic paths for future clinical advancements. In this narrative review, we summarize new evidence showing that brain damage and cognitive dysfunction are linked to T1D and delineate the role of altered glycemic control, neuronal loss and immune dysregulation. We also discuss novel therapeutic approaches that target the aforementioned mechanisms and may help prevent the onset of neurodegenerative disorders in individuals with T1D.
{"title":"Metabolic and immune dysfunction at the crossroads between type 1 diabetes and neurodegeneration","authors":"Francesca D'Addio , Loredana Bucciarelli , Maria Elena Lunati , Paolo Fiorina","doi":"10.1016/j.metabol.2025.156471","DOIUrl":"10.1016/j.metabol.2025.156471","url":null,"abstract":"<div><div>A growing body of evidence suggests that neurogenerative disorders are increasingly common in individuals with type 1 diabetes (T1D) and should be considered part of the heterogeneous impairment of the nervous system linked to the T1D condition. The already established association between brain health and blood glucose metabolic control pushes to normalize glycemia in individuals with neurodegenerative diseases as well as in those with T1D. Normoglycemia has, indeed, been associated with reduced brain atrophy and preserved neuronal plasticity and function. Interestingly, immune dysregulation recently demonstrated in neurodegenerative diseases may be highly relevant given the autoimmune nature of T1D. Poor glycemic control and a disrupted immune response may act as common pathogenic mechanisms that increase the incidence of neurodegenerative disorders in individuals with T1D and may unveil new diagnostic and therapeutic paths for future clinical advancements. In this narrative review, we summarize new evidence showing that brain damage and cognitive dysfunction are linked to T1D and delineate the role of altered glycemic control, neuronal loss and immune dysregulation. We also discuss novel therapeutic approaches that target the aforementioned mechanisms and may help prevent the onset of neurodegenerative disorders in individuals with T1D.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"176 ","pages":"Article 156471"},"PeriodicalIF":11.9,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145794290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-10DOI: 10.1016/j.metabol.2025.156466
Guanghong Jia , William P. Fay , Christos S. Mantzoros , Michael A. Hill
{"title":"ALDH2 variants – a role in cardiometabolic syndrome","authors":"Guanghong Jia , William P. Fay , Christos S. Mantzoros , Michael A. Hill","doi":"10.1016/j.metabol.2025.156466","DOIUrl":"10.1016/j.metabol.2025.156466","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"176 ","pages":"Article 156466"},"PeriodicalIF":11.9,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145743326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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