American journal of physiology. Cell physiology最新文献

{"title":"Cdc42 is crucial for the early regulation of hepatic stellate cell activation.","authors":"Hideto Yuasa, Tsutomu Matsubara, Hayato Urushima, Atsuko Daikoku, Hiroko Ikenaga, Chiho Kadono, Masahiko Kinoshita, Kenjiro Kimura, Takeaki Ishizawa, Keisuke Ohta, Norifumi Kawada, Kazuo Ikeda","doi":"10.1152/ajpcell.00987.2024","DOIUrl":"10.1152/ajpcell.00987.2024","url":null,"abstract":"<p><p>The activation of hepatic stellate cells (HSCs) from a quiescent state is a cause of liver fibrosis and a therapeutic target. HSCs are resident mesenchymal cells located in the space of Disse, exhibiting specialized morphological characteristics such as a stellate shape, large lipid droplets, and direct adhesions to hepatocytes via microprojections called HSC spines. Morphological alterations in HSCs play a crucial role in initiating their activation. However, the mechanisms regulating these changes remain unexplored. In this study, we analyzed the morphological alterations associated with HSC activation in vivo using carbon tetrachloride treatment and identified the key factors regulating these changes in vitro. Following carbon tetrachloride treatment, HSCs exhibited shortened cell processes and HSC spines, adopting an oval shape. Subsequently, the HSCs underwent further morphological changes into two activated forms: flattened and complex shapes. In vitro, activation of cell division cycle 42 (Cdc42) maintained the morphological characteristics of quiescent HSCs. Cdc42 activation in HSC cell lines inhibited the expression of markers associated with activated HSCs. Cdc42 inhibitor treatment in vivo prevented quiescent HSCs from maintaining their morphological characteristics and hindered activated HSCs from reverting to the quiescent state. In addition, HSCs around fibrotic areas in the human liver exhibited morphological alterations indicative of early activation. These findings demonstrate that Cdc42 is a crucial regulator of morphological and molecular alterations associated with HSC activation, identifying it as a novel target for the development of therapeutic agents against liver fibrosis.<b>NEW & NOTEWORTHY</b> The activation of hepatic stellate cells from a quiescent state is a cause and a therapeutic target for liver fibrosis. Morphological alterations in the hepatic stellate cells play a critical role in initiating their activation. However, the mechanisms that regulate these alterations remain unexplored. Our results indicate that cell division cycle 42 is a crucial regulator of hepatic stellate cell activation and a novel target for the development of therapeutic agents against liver fibrosis.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C757-C775"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increasing cellular NAD⁺ protects hepatocytes against palmitate-induced lipotoxicity by preventing PARP-1 inhibition and the mTORC1-p300 pathway activation.","authors":"Rui Guo, Yanhui Li, Qing Song, Rong Huang, Xiaodong Ge, Natalia Nieto, Yuwei Jiang, Zhenyuan Song","doi":"10.1152/ajpcell.00946.2024","DOIUrl":"10.1152/ajpcell.00946.2024","url":null,"abstract":"<p><p>Hepatic lipotoxicity, resulting from excessive lipid accumulation in hepatocytes, plays a central role in the pathogenesis of various metabolic liver diseases. Despite recent progress, the precise mechanisms remain incompletely understood. Using excessive exposure to palmitate in hepatocytes as our primary experimental model and mice studies, we aimed to uncover the mechanisms behind hepatic lipotoxicity, thereby developing potential treatments. Our data reveal for the first time that exposure to palmitate leads to downregulated expression of poly (ADP-ribose) polymerase 1 (PARP-1) in hepatocytes, inhibiting its enzymatic activity. Whereas inhibiting PARP-1 worsens palmitate-induced hepatotoxicity, preventing PARP-1 suppression, using nicotinamide adenine dinucleotide (NAD⁺) precursors, nicotinamide <i>N</i>-methyltransferase (NNMT) inhibitors, or a poly(ADP-ribose) glycohydrolase (PARG) inhibitor, prevents it. Moreover, we uncover that PARP-1 suppression contributes to palmitate-triggered mechanistic target of rapamycin complex 1 (mTORC1) activation, which has been previously reported by us to contribute to palmitate-induced hepatocyte cell death. Furthermore, our results identify p300 as a downstream target of mTORC1 activation upon palmitate exposure. Importantly, p300 inhibition via either pharmacological or genetic approaches protects against palmitate hepatotoxicity. In addition, we provide evidence that the toll-like receptor 4 (TLR4)-nuclear factor κB (NF-κB) pathway activation in response to palmitate plays a mechanistic role in mediating palmitate-induced PARP-1 downregulation in that both TLR4 antagonist and NF-κB inhibitors prevent palmitate-induced PARP-1 reduction and protect against hepatocyte cell death. In conclusion, our study presents new evidence that the PARP-1-mTORC1-p300 pathway serves as a novel molecular mechanism underlying palmitate-induced hepatic lipotoxicity. Targeting the PARP-1 pathway by increasing cellular NAD⁺ availability either through its precursor supplementation or by inhibiting its degradation represents a promising therapeutic approach for treating hepatic lipotoxicity.<b>NEW & NOTEWORTHY</b> This study explores the mechanisms of palmitate-induced hepatotoxicity, highlighting the role of PARP-1 downregulation in triggering the mTORC1-p300 pathway and resultant hepatocyte cell death. It further reveals that enhancing cellular NAD⁺ levels through either precursor supplementation or NNMT inhibitors prevents lipotoxicity by restoring PARP-1 activity. Finally, the study identifies that the TLR4-NF-κB activation mediates palmitate-induced PARP-1 suppression and offers potential therapeutic insights for metabolic liver diseases caused by lipotoxicity.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C776-C790"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic T-cell phenotypes: from bioenergetics to function.","authors":"Nouria Jantz-Naeem, Nese Guvencli, Romy Böttcher-Loschinski, Martin Böttcher, Dimitrios Mougiakakos, Sascha Kahlfuss","doi":"10.1152/ajpcell.00478.2024","DOIUrl":"10.1152/ajpcell.00478.2024","url":null,"abstract":"<p><p>It is well known that T-cell metabolism and function are intimately linked. Metabolic reprogramming is a dynamic process that provides the necessary energy and biosynthetic precursors while actively regulating the immune response of T cells. As such, aberrations and dysfunctions in metabolic (re)programming, resulting in altered metabolic endotypes, may have an impact on disease pathology in various contexts. With the increasing demand for personalized and highly specialized medicine and immunotherapy, understanding metabolic profiles and T-cell subset dependence on specific metabolites will be crucial to harness the therapeutic potential of immunometabolism and T cell bioenergetics. In this review, we dissect metabolic alterations in different T-cell subsets in autoimmune and viral inflammation, T cell and non-T-cell malignancies, highlighting potential anchor points for future treatment and therapeutic exploitation.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1062-C1075"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143412966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of TGF-β/SMAD/YAP/TAZ signaling in skeletal muscle fibrosis.","authors":"Felipe S Gallardo, Meilyn Cruz-Soca, Alexia Bock-Pereda, Jennifer Faundez-Contreras, Cristian Gutiérrez-Rojas, Alessandro Gandin, Veronica Torresan, Juan Carlos Casar, Andrea Ravasio, Enrique Brandan","doi":"10.1152/ajpcell.00541.2024","DOIUrl":"10.1152/ajpcell.00541.2024","url":null,"abstract":"<p><p>Skeletal muscle fibrosis is strongly associated with the differentiation of its resident multipotent fibro/adipogenic progenitors (FAPs) toward the myofibroblast phenotype. Although transforming growth factor type β (TGF-β) signaling is well-known for driving FAPs differentiation and fibrosis, due to its pleiotropic functions its complete inhibition is not suitable for treating fibrotic disorders such as muscular dystrophies. Here, we describe that TGF-β operates through the mechanosensitive transcriptional regulators Yes-associated protein (YAP)/ transcriptional coactivator with PDZ-binding motif (TAZ) to determine the myofibroblast fate of FAPs and skeletal muscle fibrosis. Spatial transcriptomics analyses of dystrophic and acute injured muscles showed that areas with active fibrosis and TGF-β signaling displayed high YAP/TAZ activity. Using a TGF-β-driven fibrotic mouse model, we found that activation of YAP/TAZ in activated FAPs is associated with the fibrotic process. Mechanistically, primary culture of FAPs reveals the remarkable ability of TGF-β1 to activate YAP/TAZ through its canonical SMAD3 pathway. Moreover, inhibition of YAP/TAZ, either by disrupting its activity (with Verteporfin) or cellular mechanotransduction (with the Rho inhibitor C3 or soft matrices), decreased TGF-β1-dependent FAPs differentiation into myofibroblasts. In vivo, administration of Verteporfin in mice limits the deposition of collagen and fibronectin, and the activation of FAPs during the development of fibrosis. Overall, our work provides robust evidence for considering YAP/TAZ as a potential target in muscular fibroproliferative disorders.<b>NEW & NOTEWORTHY</b> The understanding of the nuclear factors governing the differentiation of muscular fibro/adipogenic progenitors (FAPs) into myofibroblasts is in its infancy. Here, we comprehensively elucidate the status, regulation, and role of the mechanotransducers Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) in the muscular fibrotic process. Our findings reveal that inhibiting cellular mechanotransduction limits FAP differentiation and the extent of muscular fibrosis exerted by transforming growth factor type β (TGF-β). This research shed new lights on the molecular mechanisms dictating the cell fate of FAPs and the muscular fibrosis.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1015-C1028"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modeling ocular surface ion and water transport by generation of lipid- and mucin-producing human meibomian gland and conjunctival epithelial cells.","authors":"Chloë Radji, Christine Barrault, Roxane Flausse, Nicolas Leveziel, Anne Cantereau, Catherine Bur, Gaëtan Terrasse, Frédéric Becq","doi":"10.1152/ajpcell.00560.2024","DOIUrl":"10.1152/ajpcell.00560.2024","url":null,"abstract":"<p><p>Despite the importance of the ocular surface in human physiology and diseases, little is known about ion channel expression, properties, and regulation in ocular epithelial cells. Furthermore, human primary epithelial cells have rarely been studied in favor of rat, mouse, and especially rabbit animal models. Here, we developed primary human meibomian gland (hMGEC) and conjunctival (hConEC) epithelial cells. We show that hConEC and hMGEC produce MUC5AC and lipids, respectively. With cell cultures maintained at the air-liquid interface, we recorded transepithelial short-circuit currents (<i>I</i>_sc) by the Ussing chamber method. We identified in the apical membrane Na⁺, Cl^-, and K⁺ ion channels; amiloride-sensitive epithelial sodium channel (ENaC), cAMP-dependent CFTR, UTP-dependent TMEM16a, and chromanol 293B-sensitive KCNQ1. At the basolateral membrane, we identified bumetanide-sensitive NKCC and barium-sensitive K⁺ channels. We also found that vasoactive intestinal peptide, concentration-dependent (EC₅₀ of 1-8 nM), stimulates the CFTR-dependent <i>I</i>_sc in both cells. Western blot analysis confirms the expression in both cell cultures of βENaC subunit, CFTR, TMEM16a, and KCNQ1 proteins. We recorded water influx by quantitative phase microscopy and identified a cAMP-dependent and mercury-sensitive water flux and identified by Western blot AQP3 and AQP5 proteins in hConEC and hMGEC. Taken together, we propose a model of the ion transports of human conjunctival and meibomian gland epithelial cells that will set the stage for future molecular dissection of the regulation of these transport proteins in the context of tear secretion and related diseases.<b>NEW & NOTEWORTHY</b> We generated human meibomian gland and conjunctival epithelial cells producing lipids and mucins. We identified ion channels including ENaC, CFTR, TMEM16a, and KCNQ1, as well as NKCC. We found that electrolyte and water flux are regulated by signaling pathways mediated by purinergic and VIP receptors. Our findings provide valuable insights into epithelial ion and water transport in the human conjunctiva and meibomian gland, enhancing understanding of these processes in both physiological and disease states.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C856-C871"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IRE1 is a promising therapeutic target in pancreatic cancer.","authors":"Denise Lucas, Tamal Sarkar, Clara Y Niemeyer, Julian C Harnoss, Martin Schneider, Moritz J Strowitzki, Jonathan M Harnoss","doi":"10.1152/ajpcell.00551.2024","DOIUrl":"10.1152/ajpcell.00551.2024","url":null,"abstract":"<p><p>[Figure: see text].</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C806-C824"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hunting glioblastoma recurrence: glioma stem cells as retrospective targets.","authors":"Sümeyra Mengüç Emir, Birnur Sinem Karaoğlan, Ramazan Kaşmer, Hilal Buse Şirin, Batuhan Sarıyıldız, Nihal Karakaş","doi":"10.1152/ajpcell.00344.2024","DOIUrl":"10.1152/ajpcell.00344.2024","url":null,"abstract":"<p><p>Glioblastoma (GBM) remains one of the most aggressive and treatment-resistant brain malignancies in adults. Standard approaches, including surgical resection followed by adjuvant radio- and chemotherapy with temozolomide (TMZ), provide only transient control, as GBM frequently recurs due to its infiltrative nature and the presence of therapy-resistant subpopulations such as glioma stem cells (GSCs). GSCs, with their quiescent state and robust resistance mechanisms, evade conventional therapies, contributing significantly to relapse. Consequently, current treatment methods for GBM face significant limitations in effectively targeting GSCs. In this review, we emphasize the relationship between GBM recurrence and GSCs, discuss the current limitations, and provide future perspectives to overwhelm the challenges associated with targeting GSCs. Eliminating GSCs may suppress recurrence, achieve durable responses, and improve therapeutic outcomes for patients with GBM.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1045-C1061"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"What are the potential mechanisms of fatigue-induced skeletal muscle hypertrophy with low-load resistance exercise training?","authors":"Luke D Flewwelling, Sarkis J Hannaian, Victor Cao, Thomas Chaillou, Tyler A Churchward-Venne, Arthur J Cheng","doi":"10.1152/ajpcell.00266.2024","DOIUrl":"10.1152/ajpcell.00266.2024","url":null,"abstract":"<p><p>High-load resistance exercise (>60% of 1-repetition maximum) is a well-known stimulus to enhance skeletal muscle hypertrophy with chronic training. However, studies have intriguingly shown that low-load resistance exercise training (RET) (≤60% of 1-repetition maximum) can lead to similar increases in skeletal muscle hypertrophy as compared with high-load RET. This has raised questions about the underlying mechanisms for eliciting the hypertrophic response with low-load RET. A key characteristic of low-load RET is performing resistance exercise to, or close to, task failure, thereby inducing muscle fatigue. The primary aim of this evidence-based narrative review is to explore whether muscle fatigue may act as an indirect or direct mechanism contributing to skeletal muscle hypertrophy during low-load RET. It has been proposed that muscle fatigue could indirectly stimulate muscle hypertrophy through increased muscle fiber recruitment, mechanical tension, ultrastructural muscle damage, the secretion of anabolic hormones, and/or alterations in the expression of specific proteins involved in muscle mass regulation (e.g., myostatin). Alternatively, it has been proposed that fatigue could directly stimulate muscle hypertrophy through the accumulation of metabolic by-products (e.g., lactate), and/or inflammation and oxidative stress. This review summarizes the existing literature eluding to the role of muscle fatigue as a stimulus for low-load RET-induced muscle hypertrophy and provides suggested avenues for future research to elucidate how muscle fatigue could mediate skeletal muscle hypertrophy.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1001-C1014"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inflammation-induced PFKFB3-mediated glycolysis promoting myometrium contraction through the PI3K-Akt-mTOR pathway in preterm birth mice.","authors":"Jing He, Xuan Li, Huihui Yu, Chenyi Xu, Ruixian Tian, Ping Zhou, Zongzhi Yin","doi":"10.1152/ajpcell.00704.2024","DOIUrl":"10.1152/ajpcell.00704.2024","url":null,"abstract":"<p><p>Inflammation is a significant risk factor for preterm birth. Inflammation enhances glycolytic processes in various cell types and contributes to the development of myometrial contractions. However, the potential of inflammation to activate glycolysis in pregnant murine uterine smooth muscle cells (mUSMCs) and its role in promoting inflammatory preterm birth remain unexplored. In this study, lipopolysaccharide was employed to establish both cell and animal inflammation models. We found that inflammation of mUSMCs during late pregnancy could initiate glycolysis and promote cell contraction. Subsequently, the inhibition of glycolysis using the glycolysis inhibitor 2-deoxyglucose can reverse inflammation-induced cell contraction. The expression of 6-phosphofructokinase 2 kinase (PFKFB3) was significantly upregulated in mUSMCs following lipopolysaccharide stimulation. In addition, lactate accumulation and enhanced contraction were observed. Inhibition of PFKFB3 reversed the lactate accumulation and enhanced contraction induced by inflammation. We also found that inflammation activated the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt)-mammalian target of the rapamycin (mTOR) pathway, leading to the upregulation of PFKFB3 expression. The PI3K-Akt pathway inhibitor LY294002 and the mTOR pathway inhibitor rapamycin effectively inhibited the upregulation of PFKFB3 protein expression, lactate production, and the enhancement of cell contraction induced by lipopolysaccharide. This study indicates that inflammation regulates PFKFB3 through the PI3K-Akt-mTOR pathway, which enhances the glycolytic process in pregnant mUSMCs, ultimately leading to myometrial contraction.<b>NEW & NOTEWORTHY</b> Expression of PFKFB3, a key enzyme in glycolysis, was significantly upregulated both in the mUSMCs and myometrium of mice during late pregnancy after lipopolysaccharide stimulation. Activation of the PI3K-Akt-mTOR pathway enhanced PFKFB3 expression, which is involved in the initiation of glycolysis. Inflammation-activated PFKFB3 via the PI3K-Akt-mTOR pathway, which enhances the cellular glycolytic process and thus promotes myometrium contraction in pregnancy.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C895-C907"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor metabolism as a factor affecting diversity in cancer cachexia.","authors":"Oliver F Bathe","doi":"10.1152/ajpcell.00677.2024","DOIUrl":"10.1152/ajpcell.00677.2024","url":null,"abstract":"<p><p>Cancer cachexia is a multifaceted metabolic syndrome characterized by muscle wasting, fat redistribution, and metabolic dysregulation, commonly associated with advanced cancer but sometimes also evident in early-stage disease. More subtle body composition changes have also been reported in association with cancer, including sarcopenia, myosteatosis, and increased fat radiodensity. Emerging evidence reveals that body composition changes including sarcopenia, myosteatosis, and increased fat radiodensity, arise from distinct biological mechanisms and significantly impact survival outcomes. Importantly, these features often occur independently, with their combined presence exacerbating poor prognoses. Tumor plays a pivotal role in driving these host changes, either by acting as a metabolic parasite or by releasing mediators that disrupt normal tissue function. This review explores the diversity of tumor metabolism. It highlights the potential for tumor-specific metabolic phenotypes to influence systemic effects, including fat redistribution and sarcopenia. Addressing this tumor-host metabolic interplay requires personalized approaches that disrupt tumor metabolism while preserving host health. Promising strategies include targeted pharmacological interventions and anticachexia agents like growth differentiation factor 15 (GDF-15) inhibitors. Nutritional modifications such as ketogenic diets and omega-3 fatty acid supplementation also merit further investigation. In addition to preserving muscle, these therapies will need to be evaluated for their capability to improve survival and quality of life. This review underscores the need for further research into tumor-driven metabolic effects on the host and the development of integrative treatment strategies to address the interconnected challenges of cancer progression and cachexia.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C908-C920"},"PeriodicalIF":5.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}