Cell Biochemistry and Function最新文献

{"title":"Melatonin Protects BEAS-2B Cells Against Hypoxia/Reoxygenation-Induced Injury By Reducing MLKL Levels, Suppressing Oxidative Stress and Preserving Mitochondrial Function","authors":"Zehra Yilmaz,&nbsp;Askin Tas,&nbsp;Ozlem Oz,&nbsp;Ismail Koyuncu,&nbsp;Ebru Temiz,&nbsp;Ozgur Yuksekdag","doi":"10.1002/cbf.70304","DOIUrl":"10.1002/cbf.70304","url":null,"abstract":"<p>Necroptosis has been demonstrated to play a role in the process of lung ischemia-reperfusion injury (LIRI) in a variety of clinical conditions, including cardiopulmonary bypass and pulmonary embolism. Melatonin has been reported to exert a protective role by reducing oxidative stress and acute inflammatory reactions in LIRI. However, the effect of melatonin on necroptosis in LIRI remains unclear. The aim of this study was to investigate whether the protective effects of melatonin against H/R-induced injury are associated with modulation of necroptosis and related changes in mitochondrial function and oxidative stress. The cells were exposed to H/R (16/4 h) or normoxia, in the absence or presence of 2.5 µM melatonin. Cell viability was determined by the MTT method, while morphological changes in BEAS-2B cells resulting from H/R exposure were evaluated by fluorescence microscopy using acridine orange/ethidium bromide (AO/EtBr) staining. Mechanistic analyses, including flow cytometry-based cell cycle assessment, apoptosis detection (Annexin V-FITC), mitochondrial membrane potential evaluation (JC-1), and reactive oxygen species (ROS) measurements, were performed on BEAS-2B cells. The level of the mixed lineage kinase domain-like pseudokinase (MLKL), a key component of the necroptosis complex, was also quantified using an enzyme-linked immunosorbent assay. In addition, the ATP, pH, and lactate levels were determined. The findings indicated that melatonin treatment reduced the H/R-induced increase in the percentage of necrotic cells and increased the percentage of viable cells (<i>p</i> &lt; 0.05). In addition, melatonin treatment reduced the increase in MLKL, ROS, and lactate levels, preserved mitochondrial membrane integrity, and increased intracellular ATP levels in BEAS-2B cells exposed to H/R (<i>p</i> &lt; 0.05). In conclusion, this study suggests that melatonin protects BEAS-2B cells against H/R-induced injury, and that this protective effect may be associated with reduced oxidative stress, preservation of mitochondrial function, and suppression of necroptosis-related signaling.</p>","PeriodicalId":9669,"journal":{"name":"Cell Biochemistry and Function","volume":"44 9","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13556524/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148910663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual miRNA-Mediated Axes Act in Concert in the Antioxidant Action of Eicosapentaenoic Acid: let-7c-3p/TFAM Drives Mitochondrial Biogenesis While miR-34c-5p/SIRT1 Potentiates Enzymatic Defenses","authors":"Haiqi Wang,&nbsp;Yanqi Lin,&nbsp;Yuanyuan Li,&nbsp;Xiaowen Wu,&nbsp;Jingyu Lin,&nbsp;Shiying Huang,&nbsp;Guiling Li","doi":"10.1002/cbf.70298","DOIUrl":"10.1002/cbf.70298","url":null,"abstract":"<p>Previous transcriptomic analysis revealed that eicosapentaenoic acid (EPA) alters miRNA expression in HepG2 cells. Two key miRNA-mRNA axes mediating EPA's antioxidant effects were identified. EPA was found to downregulate let-7c-3p, which directly targets mitochondrial transcription factor A (TFAM). Inhibiting let-7c-3p or overexpressing TFAM enhanced antioxidant capacity, reduced reactive oxygen species, improved mitochondrial function, and promoted mitochondrial biogenesis. In parallel, EPA was found to upregulate miR-34c-5p, which directly targets NAD-Dependent Protein Deacetylase Sirtuin (SIRT1). This repression of SIRT1 is associated with increased activities of antioxidant enzymes, including catalase, superoxide dismutase, and glutathione peroxidase. These findings indicate a dual-miRNA mechanism through which EPA alleviates oxidative stress via coordinated enhancement of mitochondrial biogenesis and enzymatic defenses.</p>","PeriodicalId":9669,"journal":{"name":"Cell Biochemistry and Function","volume":"44 9","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13551511/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148905298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"S100 Calcium-Binding Protein 16 (S100A16) Promotes Hepatic Stellate Cell Activation Via Erb-B2 Receptor Tyrosine Kinase 2 (ERBB2)-mediated Glycolysis to Facilitate Liver Fibrosis","authors":"Shiyu Ou,&nbsp;Xiaoling Tang,&nbsp;Juan Liu,&nbsp;Rong Ouyang,&nbsp;Shijiang Huang,&nbsp;Shuwen Weng,&nbsp;Jinping Qin,&nbsp;Dingheng Liang,&nbsp;Ling Du,&nbsp;Zhongzhuan Li","doi":"10.1002/cbf.70299","DOIUrl":"10.1002/cbf.70299","url":null,"abstract":"<p>Hepatic stellate cell (HSC) activation is a key mediator in hepatic fibrosis, with glycolysis serving a key regulatory function. S100 calcium-binding protein 16 (S100A16) has been associated with various pathologies; however, its function and underlying mechanisms in liver fibrosis remains elusive. This study aimed to elucidate the functional role of S100A16 in HSC activation and its interaction with Erb-B2 receptor tyrosine kinase 2 (ERBB2)-mediated glycolysis. Transforming growth factor-β1 (TGF-β1)-stimulated human liver stellate cells (LX2) and carbon tetrachloride (CCl₄)-induced mice were used as in vitro and in vivo models, respectively. Cell proliferation and alpha-smooth muscle actin (α-SMA) expression were detected by Cell Counting Kit-8 (CCK-8) assay and immunofluorescence. Glycolysis was detected via measuring the extracellular acidification rate (ECAR), lactate production, glucose uptake, and glycolytic enzyme levels. Molecular interactions were analyzed through bioinformatics and co-immunoprecipitation. Liver injury and fibrosis were assessed using hematoxylin and eosin (H&amp;E)/Masson staining. Expression of S100A16, ERBB2, and fibrosis markers were quantified using quantitative real-time PCR (qRT-PCR) and Western blot. S100A16 was upregulated in fibrotic liver tissues and TGF-β1-stimulated LX2 cells. TGF-β1 increased lactate production and glycolysis, whereas S100A16 knockdown produced the opposite effects. Additionally, TGF-β1 enhanced cell proliferation and upregulated α-SMA, Collagen 1, and Fibronectin levels, but these effects were attenuated by either S100A16 knockdown or glycolysis inhibition. S100A16 interacted with ERBB2 and promoted its expression. ERBB2 knockdown reduced TGF-β1-induced glycolysis and HSC activation, along with reduced cell proliferation, effects that were inhibited by S100A16 overexpression. Furthermore, S100A16 knockdown ameliorated CCl₄-induced liver injury and fibrosis, decreased serum lactate levels, and reduced S100A16 and ERBB2 expression, thereby suppressing glycolysis. Collectively, S100A16 promotes HSC activation and liver fibrosis through ERBB2-mediated glycolysis, highlighting the S100A16-ERBB2-glycolysis axis as a potential therapeutic target.</p>","PeriodicalId":9669,"journal":{"name":"Cell Biochemistry and Function","volume":"44 9","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13549247/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148900281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Syntaxin-3 Regulates Tight Junction Assembly in Human Retinal Pigment Epithelium","authors":"Athira Ramesh,&nbsp;Suganya Sivagurunathan,&nbsp;Navya Valavath Baburajan,&nbsp;Subbulakshmi Chidambaram","doi":"10.1002/cbf.70294","DOIUrl":"10.1002/cbf.70294","url":null,"abstract":"<p>The retinal pigment epithelium (RPE) consists of polarized epithelial cells, serving as a support system for photoreceptor maintenance, where the polarity is contributed by the distribution of syntaxins (STX) within the cell. STX3, a known regulator of apical trafficking in epithelial cells, was previously understood to be absent in human RPE cells, with its functions thought to be compensated by STX1A. However, our results on SNARE mRNA expression profile in RPE detected the presence of 2 splice variants of STX3. Further investigation in donor retina, primary hRPE, and ARPE-19 cells revealed detectable levels of STX3 mRNA and protein. STX3 knockdown in ARPE19 resulted in a significant reduction of tight junction (TJ) proteins, compromising TJ assembly, highlighting the critical role of STX3 in maintaining RPE integrity. In addition, immunoprecipitation followed by LC-MS/MS analysis revealed that STX3 and STX1A have a distinct novel protein interactome in RPE. This study identified unique and shared interactants for STX3 and STX1A, suggesting a broader role for RPE beyond its traditional photoreceptor support function. This further emphasizes the biological significance of STX1A and STX3 in maintaining retinal homeostasis, which could facilitate the development of novel therapeutic strategies for retinal disorders.</p>","PeriodicalId":9669,"journal":{"name":"Cell Biochemistry and Function","volume":"44 9","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13543195/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148890833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Organelle Crosstalk and Metabolic Reprogramming in Idiopathic Pulmonary Fibrosis: Mechanisms and Therapeutic Implications","authors":"Yining Zhang,&nbsp;Ling Teng,&nbsp;Limin Gong,&nbsp;Yuandong Fu,&nbsp;Minyi Qian","doi":"10.1002/cbf.70295","DOIUrl":"10.1002/cbf.70295","url":null,"abstract":"<p>Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease of unknown cause, marked by excessive deposition of extracellular matrix (ECM) components such as collagen. This pathological accumulation results in progressive destruction of the lung architecture and ultimately leads to respiratory failure. Growing evidence indicates that dysfunction across multiple cell types is an important driver of IPF. Nevertheless, its underlying pathobiology remains incompletely understood. The normal integrity of organelles is critical for cellular function, and in different IPF lung cells, such as alveolar epithelial cells (AECs), fibroblasts, and macrophages, we found dysfunctional development of key organelles and metabolic reprogramming changes driving malignant progression of pulmonary fibrosis. This review summarizes the contributions of key organelles—mitochondria, the endoplasmic reticulum, lysosomes, and peroxisomes—and functional changes in metabolic reprogramming during IPF progression. We further clarify the core mechanisms of how inter-organelle network disruptions drive fibrosis, with the goal of identifying critical organelle nodes to disrupt pathogenic metabolic reprogramming and ultimately provide a rationale for developing new treatments.</p>","PeriodicalId":9669,"journal":{"name":"Cell Biochemistry and Function","volume":"44 9","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13543056/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148890822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reactive Oxygen Species in Breast Cancer: From Redox Dysregulation to ROS-Responsive Therapeutics","authors":"Marija Nikolovska,&nbsp;Radoslav Stojchevski,&nbsp;Aleksandar Eftimov,&nbsp;Mitko Mladenov,&nbsp;Dimiter Avtanski,&nbsp;Nikola Hadzi-Petrushev","doi":"10.1002/cbf.70301","DOIUrl":"10.1002/cbf.70301","url":null,"abstract":"<p>Breast cancer is the most frequently diagnosed malignancy among women worldwide, with 2.3 million new cases and approximately 670,000 deaths reported in 2022 alone. Despite advances in therapy, metastasis and acquired drug resistance remain major clinical challenges. Reactive oxygen species (ROS) play a dual role in breast cancer biology: physiological levels sustain normal cellular signaling, moderately elevated levels promote tumorigenesis through DNA damage, proto-oncogene activation, and tumor suppressor inactivation, while excessive accumulation can trigger cancer cell death. This review examines how redox dysregulation contributes to breast cancer initiation and progression through key signaling pathways, including phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), mitogen-activated protein kinase (MAPK), and Kelch-like ECH-associated protein 1–nuclear factor erythroid 2-related factor 2 (Keap1-Nrf2), as well as apoptotic cascades. We evaluate the evidence for dietary and synthetic antioxidants—melatonin, curcumin, vitamins C and E, and carotenoids—as chemopreventive and adjuvant agents, highlighting both their therapeutic promise and the conflicting data on their safety during cancer treatment. We further discuss emerging ROS-responsive nanoagents for targeted drug delivery and immunotherapy, and strategies to exploit redox vulnerabilities in multidrug-resistant breast cancer cells, including induction of ferroptosis, an iron-dependent cell death pathway driven by lipid peroxide accumulation that has emerged as a promising vulnerability in therapy-resistant and mesenchymal-phenotype tumors. Recent advances in machine learning and multi-omics integration, which have begun to identify redox-related gene signatures with prognostic and immunotherapy-predictive value, further point toward precision redox oncology as an emerging clinically actionable framework. By integrating molecular mechanisms with translational advances, this review identifies current gaps and future directions for ROS-targeted therapeutic strategies in breast cancer.</p>","PeriodicalId":9669,"journal":{"name":"Cell Biochemistry and Function","volume":"44 9","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13543335/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148890789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Histone Post-Translational Modifications Regulating Ferroptosis: The Molecular Mechanisms and Disease Associations","authors":"Xiaoqian Tang,&nbsp;Haodang Luo,&nbsp;Siqi Gao,&nbsp;Xiaocheng Liu,&nbsp;Qing Sun,&nbsp;Yanhua Zeng","doi":"10.1002/cbf.70300","DOIUrl":"10.1002/cbf.70300","url":null,"abstract":"<p>Ferroptosis is a form of programmed cell death characterized by iron-dependent phospholipid peroxidation and is implicated in a wide range of human diseases. Emerging evidence highlights the critical role of epigenetic regulation in this process. Dysregulation of histone post-translational modifications (HPTMs) is increasingly recognized as a pivotal mechanism linking metabolic reprogramming to various pathological conditions. HPTMs constitute one of the key epigenetic regulatory mechanisms and mediate ferroptosis by modulating the transcription of core ferroptosis-related genes. This review systematically summarizes site-specific HPTMs, including histone methylation, acetylation, ubiquitination, phosphorylation, lactylation, and β-hydroxybutyrylation. Furthermore, we elucidate how infectious diseases, tumors, and chronic non-infectious conditions drive disease progression via HPTMs-dependent regulation of ferroptosis. A comprehensive dissection of these epigenetic regulatory networks may facilitate the development of combinatorial therapeutic strategies targeting HPTMs and ferroptosis inducers, thereby providing new insights into the treatment of ferroptosis-associated disorders.</p>","PeriodicalId":9669,"journal":{"name":"Cell Biochemistry and Function","volume":"44 9","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13539949/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148886125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Revising NHE-1: From Cardiac Homeostasis to Heart Failure and Future Drug Development","authors":"Vasileios Bouratzis,&nbsp;Nikoleta Douskou,&nbsp;Nikolaos P. Tzavellas,&nbsp;Yannis V. Simos,&nbsp;Petros Bozidis,&nbsp;Konstantinos I. Tsamis,&nbsp;Georgios S. Markopoulos,&nbsp;Dimitrios Peschos,&nbsp;Lampros Lakkas","doi":"10.1002/cbf.70291","DOIUrl":"https://doi.org/10.1002/cbf.70291","url":null,"abstract":"<p>NHE-1 is a Na⁺/H⁺ exchanger that receives phosphorylation signals, binds calmodulin and responds to neurohormonal input from angiotensin II, endothelin-1, and adrenergic pathways. In cardiac myocytes, NHE-1 maintains pH homeostasis and couples to Na⁺/Ca²⁺ exchange and mitochondrial ion handling. During heart disease sustained activation drives intracellular Na⁺ accumulation, promoting Ca²⁺ overload and mitochondrial dysfunction. Oxidative stress then creates amplifying cycles that activate signaling pathways resulting to arrhythmias and fibrosis. Clinical trials failed despite preclinical promise, due to a variety of false experimental factors. SGLT2 inhibitors appear to modulate NHE-1 indirectly through metabolic reprogramming and hemodynamic effects rather than direct blockade. Current approaches use structural data to target regulatory sites and phosphorylation-dependent conformational states instead of the transport pore. Translation to patients will require biomarkers identifying pathological hyperactivity and better patient stratification methods. Here, we try to review NHE-1 structure, regulation, and physiology that may influence research on future drug development.</p>","PeriodicalId":9669,"journal":{"name":"Cell Biochemistry and Function","volume":"44 9","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cbf.70291","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148860069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Significance of cGAS-STING Signaling in Response to Oncogenic Viruses","authors":"Limei Guo,&nbsp;Li Li,&nbsp;Fang Wang,&nbsp;Wen Liu,&nbsp;Yan Zhang","doi":"10.1002/cbf.70296","DOIUrl":"https://doi.org/10.1002/cbf.70296","url":null,"abstract":"<p>The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway, as a key DNA sensor, plays a significant role in the regulation of innate immune responses. This pathway can be activated by sensing abnormal DNA, and is of great significance for resisting the invasion of pathogenic microorganisms and maintaining tissue homeostasis. In addition, the cGAS-STING pathway plays a dual role in cancer, and oncogenic viruses can cause cell carcinogenesis in the body through multiple mechanisms, thereby affecting human health. This manuscript reviews the vital role of cGAS-STING in the immune process, as well as the fact that viruses causing human tumor lesions can activate cGAS-STING, leading to virus inhibition and further preventing the occurrence and development of related cancers, and the paradoxically promoted progression of related cancers by viruses through cGAS-STING. And summarize the agonists and inhibitors that act in different ways based on the activation mechanism of cGAS-STING.</p>","PeriodicalId":9669,"journal":{"name":"Cell Biochemistry and Function","volume":"44 9","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cbf.70296","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148860128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interactions Between E3 Ubiquitin Ligases and Deubiquitinases in AKT Regulation: Implications in Skeletal Muscle Homeostasis","authors":"Rajesh Dabur","doi":"10.1002/cbf.70297","DOIUrl":"https://doi.org/10.1002/cbf.70297","url":null,"abstract":"<p>AKT (protein kinase B, PKB) coordinates the balance between anabolic and catabolic signaling in skeletal muscle through distinct ubiquitin chain types. Some E3 ubiquitin ligases (E3s) and deubiquitinases (DUBs) form stable binary complexes via non-catalytic interfaces, adding a regulatory layer unavailable to either enzyme alone. This mechanistic synthesis review presents a systematic literature analysis (inception to May 2026; 26 eligible studies). It identified four E3–DUB pairs proposed to regulate AKT in skeletal muscle. These are TRAF6–CYLD (plasma-membrane K63-ubiquitination), MUL1–USP9X (mitochondrial K48-ubiquitination of AKT2), CHIP–UCH37 (proteasome-proximal quality control), and SCF-Skp2–USP37 (PHLPP1/2-dependent control of AKT Ser473 phosphorylation). All four interfaces are structurally separate from the catalytic sites and are regulated by upstream kinase phosphorylation. Evidence for the four pairs is markedly uneven. TRAF6–CYLD is supported by endogenous co-immunoprecipitation and functional data in muscle models. CHIP and UCH37 each act on AKT-related substrates independently and are individually well documented, but a direct CHIP–UCH37 interaction has not itself been demonstrated. SCF-Skp2–USP37 interaction data rest on a real but non-muscle direct interaction, whereas MUL1–USP9X has no reported direct interaction at all; CHIP–UCH37, SCF-Skp2–USP37, and MUL1–USP9X are therefore all presented as testable hypotheses of varying strength. In chronic atrophy, available data are consistent with disruption of these complexes contributing to AKT suppression through parallel, largely independent mechanisms. However, simultaneous disruption of all four has not been demonstrated in a single system. Available gene expression and protein datasets from sarcopenic muscle broadly support these predictions, though direct experimental validation in human tissue remains pending. This complex-centric framework recasts AKT ubiquitination as an integrated regulatory framework. Each structurally autonomous interface may represent a potentially distinct target for muscle-wasting conditions that currently lack approved therapies.</p>","PeriodicalId":9669,"journal":{"name":"Cell Biochemistry and Function","volume":"44 9","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cbf.70297","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148860129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}