IUBMB Life最新文献

{"title":"The Receptor for Advanced Glycation End Products: Regulation and Implications in Metabolic Diseases","authors":"Ga Young Lee,&nbsp;Sung Nim Han","doi":"10.1002/iub.70137","DOIUrl":"10.1002/iub.70137","url":null,"abstract":"<div>\u0000 \u0000 <p>Receptor for advanced glycation end-products (RAGE) was originally identified as a receptor for advanced glycation end-products; however, it can also bind a broader range of damage-associated molecular patterns, including S100 proteins, high mobility group box 1, and amyloid-β. Ligand-induced RAGE activation promotes receptor oligomerization and recruitment of diaphanous-related formin-1, which activates several intracellular cascades, leading to the production of inflammatory mediators and reactive oxygen species. RAGE expression is upregulated in disease-associated tissues, including adipose tissue in diabetes and microglia and neurons in Alzheimer's disease, and the mechanisms by which RAGE activation contributes to pathogenesis are disease-specific. The review summarizes the expression and activation of RAGE, and the potential mechanisms through which RAGE contributes to disease pathogenesis. We further discuss current and emerging strategies for modulating RAGE signaling and highlight their therapeutic potential in the prevention and treatment of RAGE-associated diseases.</p>\u0000 </div>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"78 10","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149181992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial Transcriptomic and CITE-Seq Analyses Identify Clearance-Defective Signatures in Psoriatic Disease","authors":"Caio Santos Bonilha","doi":"10.1002/iub.70138","DOIUrl":"10.1002/iub.70138","url":null,"abstract":"<div>\u0000 \u0000 <p>Psoriatic lesions contain sustained inflammatory stress, but whether death-associated tissue activity is matched by adequate clearance capacity remains poorly defined. To address this, spatial transcriptomics was used to define clearance imbalance in psoriatic skin, with peripheral CITE-seq assessing circulating myeloid clearance states. Within leucocyte-rich tissue regions, stress-death and clearance-capacity modules identified clearance-competent niches, marked by matched stress and clearance activity and clearance-defective niches, marked by stress-death activity without comparable clearance capacity. This revealed that lesional psoriatic skin shows a selective epidermal clearance imbalance, with increased clearance defect, a higher defective-to-competent niche ratio and distinct clearance-defective transcriptional programming enriched for stress-processing and stress-response pathways. The clinical relevance of this epidermal axis was supported by a correlation between epidermal, but not dermal, clearance defect and psoriasis severity. Within this severity-linked compartment, a preserved monocyte/macrophage-rich burden masked reduced clearance-associated programming, indicating that defective epidermal niches retain myeloid-rich spatial contexts without matched clearance capacity. Peripheral profiling extended this axis to circulation, where psoriatic arthritis showed increased clearance defect scores in mononuclear myeloid cells and a clearance-defective surface phenotype linked to reduced efferocytosis-associated capacity. Together, these findings define clearance-defective psoriatic inflammation as an epidermal tissue programme with convergent circulating myeloid clearance defects in higher burden disease.</p>\u0000 </div>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"78 10","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149166517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to “MMP9 Knockout by CRISPR-Cas9 Reduces Bladder Cancer Malignancy But Does Not Synergize With BCG and Anti-PD-L1 in an Orthotopic Mouse Model”","authors":"","doi":"10.1002/iub.70134","DOIUrl":"10.1002/iub.70134","url":null,"abstract":"<p>\u0000 <span>J. A. D. Camargo</span>, <span>M. C. Lee</span>, <span>M. M. D. Souza</span>, et al., “ <span>MMP9 Knockout by CRISPR-Cas9 Reduces Bladder Cancer Malignancy But Does Not Synergize With BCG and Anti-PD-L1 in an Orthotopic Mouse Model</span>,” <i>IUBMB Life</i> <span>78</span>, no. <span>9</span> (<span>2026</span>): e70130, https://doi.org/10.1002/iub.70130.\u0000 </p><p>In the originally published article, author Giovana Vilas Boas Caetano was incorrectly given as Giovana Caetano Vilas Boas. The online version of the article has been updated.</p><p>We apologize for this error.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"78 10","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/iub.70134","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149136641","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":"Icariin Protects Against Mitochondrial Damage and Ferroptosis-Related Injury in Synovial Fibroblast-Like Synoviocytes Through SUMO1-Dependent Regulation of SIRT1.","authors":"Zhiming Wu, Zeqing Mao, Jian Guo, Mingfeng Xiong, Yifen Zhou, Xiaobo Zhu","doi":"10.1002/iub.70136","DOIUrl":"https://doi.org/10.1002/iub.70136","url":null,"abstract":"<p><p>Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and progressive joint destruction, in which fibroblast-like synoviocytes (FLSs) play a central pathogenic role. Ferroptosis and oxidative stress-driven mitochondrial dysfunction have recently been implicated in synovial cell injury during RA progression. Sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide-dependent deacetylase, is known to regulate inflammation, redox homeostasis, and cell survival; however, the upstream regulatory mechanisms controlling SIRT1 function and their relevance to ferroptosis in RA remain poorly defined. Primary rat FLSs and a complete Freund's adjuvant (CFA)-induced adjuvant arthritis (AA) rat model were used. SIRT1 transcription, protein expression, subcellular localization, and enzymatic activity were assessed using quantitative real-time PCR, Western blotting, immunofluorescence, and enzymatic assays. Oxidative stress, mitochondrial dysfunction, lipid peroxidation, and ferroptosis-related parameters were evaluated using biochemical assays and fluorescence-based probes. SUMO1 expression was manipulated by knockdown and overexpression approaches, and the interaction between SUMO1 and SIRT1 was examined by co-IP.Inflammatory stimulation with IL-1β impaired SIRT1 transcriptional expression, reduced its nuclear localization, and suppressed its enzymatic activity in FLSs, accompanied by enhanced reactive oxygen species accumulation, mitochondrial dysfunction, lipid peroxidation, and ferroptosis-related changes. ICA treatment restored SIRT1 expression and activity while alleviating oxidative stress and ferroptotic injury. ICA upregulated SUMO1 expression, while Co-IP analysis demonstrated an association between SUMO1 and SIRT1. SUMO1-dependent regulation was associated with increased SIRT1 nuclear localization and enzymatic activity. Disruption of SUMO1 expression or pharmacological inhibition of SIRT1 suppressed the protective effects of ICA in FLSs. Consistent regulatory effects were observed in arthritic rats following ICA administration. These findings support the involvement of SUMO1/SIRT1 regulation in ferroptosis-related injury and mitochondrial dysfunction in RA-associated synovial cells. ICA exerts protective effects by restoring coordinated SIRT1 regulation at multiple functional levels, highlighting SIRT1-centered pathways as potential therapeutic targets for RA.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"78 10","pages":"e70136"},"PeriodicalIF":3.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149224055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Causal Associations Between Plasma Metabolites and Stroke Risk Identified by Mendelian Randomization","authors":"Lu Ding,&nbsp;Zhenyuan Li,&nbsp;Fuyuan Deng,&nbsp;Baochao Fan,&nbsp;Yifan Wu,&nbsp;Guangpeng Zhang,&nbsp;Jinchun Zeng,&nbsp;Liming Lu","doi":"10.1002/iub.70124","DOIUrl":"https://doi.org/10.1002/iub.70124","url":null,"abstract":"<div>\u0000 \u0000 <p>Stroke is a leading cause of global mortality and morbidity, yet its underlying metabolic mechanisms remain largely undefined. Elucidating the causal role of blood metabolites in stroke pathogenesis is crucial for developing effective interventions. This study employed a two-sample Mendelian randomization (MR) framework to investigate the causal relationships between 1400 plasma metabolites and the risk of stroke and its subtypes. We integrated genome-wide association study (GWAS) data on metabolites from 3441 to 8299 European-ancestry individuals in the Canadian Longitudinal Study on Aging (CLSA) with European-ancestry stroke GWAS data from the MEGASTROKE consortium. IVW associations were interpreted together with Benjamini–Hochberg false-discovery-rate (FDR) correction, sensitivity analyses, and mRnd power estimates. The IVW screening analysis identified 235 nominal associations (<i>P</i>_IVW &lt; 0.05) across 124 metabolites and ratios. Among the final prioritized findings, plasma free asparagine (OR = 0.852, 95% CI: 0.782–0.929, FDR = 0.033) and the glutamine-to-asparagine ratio (OR = 1.148, 95% CI: 1.068–1.235, FDR = 0.033) showed FDR-significant associations with cardioembolic stroke. Additional associations for steroid sulfates, bile-acid conjugates, and octadecenedioylcarnitine were nominally significant and supported by directionally consistent sensitivity analyses but did not pass FDR correction. Our MR analysis prioritizes amino-acid metabolism in cardioembolic stroke and suggests additional lipid-related metabolic pathways for follow-up. Because several associations were exploratory after FDR correction and all GWAS datasets were restricted to European ancestry, replication in larger and more diverse populations is warranted before clinical translation.</p>\u0000 </div>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"78 10","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149083910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predicting Hormesis Effects of GenX in Zebrafish via Interpretable Machine Learning: Insights From SHAP Analysis","authors":"Yanwei Xu,&nbsp;Fan Mo,&nbsp;Boda Wang,&nbsp;Jingyuan Dai,&nbsp;Chenxi Zhang,&nbsp;Yue Yang,&nbsp;Yongchang Shang,&nbsp;Haibo Li","doi":"10.1002/iub.70135","DOIUrl":"https://doi.org/10.1002/iub.70135","url":null,"abstract":"<div>\u0000 \u0000 <p>Hexafluoropropylene oxide-dimer acid (GenX), a prominent alternative to legacy per- and polyfluoroalkyl substances (PFAS), poses a significant challenge to traditional linear risk assessment models due to its ability to induce hormesis—a biphasic “low-dose stimulation, high-dose inhibition” response. This study established an interpretable machine learning (ML) framework to identify and predict GenX-induced non-monotonic dose–response (NMDR) relationships in zebrafish (<i>Danio rerio</i>). By integrating 263 independent experimental records across 11 biological categories, we benchmarked 6 mL paradigms, with the CatBoost-based Master Model demonstrating exceptional predictive fidelity (AUC = 0.977; Accuracy = 91.25%). Mechanistic interpretation via SHAP (SHapley Additive exPlanations) analysis revealed that “Effect Measurement” and “Biological Category” are the primary determinants of hormetic responses. Specifically, the immune, endocrine, and reproductive systems, alongside neurobehavioral endpoints, exhibited the highest sensitivity to low-dose stimulation. Structure–activity relationship (SAR) analysis identified lipophilicity and surface distribution descriptors (<i>MolLogP, SlogP_VSA3)</i>, electrostatic state and surface area descriptors (<i>VSA_EState</i> series), and topological connectivity index (<i>Chi1v</i>) as core structural drivers of hormesis. These findings suggest that GenX-induced hormesis stems from a strategic metabolic trade-off, where optimized electronic distribution and lipid-mediated transport trigger adaptive overcompensation via signaling pathways like oxidative stress. This research provides a quantitative tool and a robust scientific basis for the ecological risk assessment of emerging PFAS alternatives, shifting the paradigm from empirical data fitting to mechanistic predictive generalization.</p>\u0000 </div>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"78 10","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149083964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oncostatin M as a Multifunctional Regulator of Breast Cancer Progression: Current Insights and Future Therapeutic Avenues","authors":"Muslem Nuseir,&nbsp;Farrukh Ismatov,&nbsp;Abdulqader Faris Abdulqader,&nbsp;Amir Abdul Kadhim,&nbsp;Malathi Hanumanthayya,&nbsp;Divya Singhal,&nbsp;Neeraj Bainsal,&nbsp;Djamila Polatova","doi":"10.1002/iub.70131","DOIUrl":"10.1002/iub.70131","url":null,"abstract":"<div>\u0000 \u0000 <p>Breast cancer (BC) constitutes the most prevalent malignancy globally, with an incidence of approximately 80%–85% for invasive ductal carcinoma (IDC) and 10%–15% for invasive lobular carcinoma (ILC), and a persistently high mortality and morbidity rate. Although IDC and ILC originate from distinct cellular lineages (ductal and lobular epithelial cells, respectively), they frequently develop in the context of hormonal dysregulation and chronic proliferative stimuli. Recent evidence accumulated over the past decade has demonstrated a role for cytokines belonging to the interleukin-6 (IL-6) family in the pathogenesis and progression of BC. These cytokines exert their effects via the activator of transcription (JAK/STAT) pathways, activating downstream Janus kinase/signal transducer, and gp130 receptor subunit activation. As a member of the IL-6 family, Oncostatin M (OSM.) is critically involved in the processes of autoimmune disorders, inflammation, and oncogenesis, particularly in BC. It has been demonstrated that the overexpression of OSM and OSM receptor (OSMR) plays a pivotal role in cancer cell remodeling and promotes cell proliferation, angiogenesis, survival, invasion, and other hallmark features of BC. However, owing to the involvement of multiple signaling pathways, OSM can exert context-dependent and even contradictory effects in certain cancer types. This review aims to examine the emerging roles of OSM in BC, elucidate its multifunctional role in tumor regulation and progression, and ultimately explore therapeutic strategies developed to modulate this cytokine in the context of BC.</p>\u0000 </div>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"78 9","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148976808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MMP9 Knockout by CRISPR-Cas9 Reduces Bladder Cancer Malignancy But Does Not Synergize With BCG and Anti-PD-L1 in an Orthotopic Mouse Model","authors":"Juliana Alves de Camargo,&nbsp;Maria Carolina Lee,&nbsp;Milena Monteiro de Souza,&nbsp;Luana Pereira da Silva,&nbsp;Giovanna Caetano Vilas Boas,&nbsp;Karina Serafim da Silva,&nbsp;Carolina Mie Mioshi,&nbsp;Ruan Cesar Aparecido Pimenta,&nbsp;Patrícia Candido,&nbsp;Iran Amorim da Silva,&nbsp;Ericka Barbosa Trarbach,&nbsp;Katia Ramos Moreira Leite,&nbsp;William Carlos Nahas,&nbsp;Sabrina Thalita dos Reis","doi":"10.1002/iub.70130","DOIUrl":"10.1002/iub.70130","url":null,"abstract":"<p>Bladder cancer (BC) is the 10th most common cancer worldwide, accounting for approximately 5% of new cases. Several factors contribute to tumor progression, including increased MMP9. Recently, CRISPR-Cas9 and immunotherapy have offered high specificity for treatments; therefore, we edited MMP9 using CRISPR-Cas9 methodology to inhibit metastatic mechanisms and evaluated potential synergy with BCG and anti-PD-L1 therapy. We performed CRISPR-Cas9 gene editing using an RNP complex in the MB49 murine BC cell line. Gene expression of MMPs, integrins, and BAX was analyzed, along with protein expression. Cells were divided into a Scramble control group and CRISPR-Cas9 for the MMP9 edited group (MMP9−/−). Female C57BL/6 mice received orthotopic BC cells (scramble and MMP9−/− groups) treated with BCG and anti-PD-L1. Statistical analyses were performed using <i>t</i> test or ANOVA. MMP9 gene and protein expression were reduced in the MMP9−/− group compared with the scramble group. No differences were observed in other MMPs. Decreased ITGB3, increased BAX gene expression, as well as reduced migration and adhesion to ECM were observed in the MMP9−/− group. Animals in the scramble group showed greater weight loss and lower survival than treated groups. Overall, MMP9 modulated key cellular mechanisms, but did not show synergistic effects with BCG and anti-PD-L1 in vivo.</p>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"78 9","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13550818/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148905827","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":"N-Acetyl Cysteine Mitigates d-Ribose-Induced Protein Glycation and Aggregation Through Multiple Protective Mechanisms","authors":"Rabia Nabi,&nbsp;Tabrez Faruqui,&nbsp;Mohd Shahnawaz Khan,&nbsp;Nouf Omar Alafaleq,&nbsp;Sahir Sultan Alvi,&nbsp;Paridhi Puri,&nbsp;Mohd Waiz,&nbsp;Mohammad Yusuf,&nbsp;Naved Ahmad,&nbsp;M. Salman Khan,&nbsp;Saheem Ahmad","doi":"10.1002/iub.70126","DOIUrl":"https://doi.org/10.1002/iub.70126","url":null,"abstract":"<div>\u0000 \u0000 <p>Advanced glycation end-products (AGEs) arise from non-enzymatic reactions between reducing sugars and proteins, contributing to oxidative stress and metabolic dysfunction. Excessive AGE accumulation is implicated in chronic diabetic complications and may also be relevant to acute metabolic disturbances encountered in emergency medicine. <i>N</i>-acetylcysteine (NAC), a naturally occurring antioxidant found in <i>Allium</i> species, has demonstrated potential to attenuate oxidative and glycation-mediated damage. The effect of NAC on <span>d</span>-ribose-induced glycation of bovine serum albumin (BSA) was investigated using multiple physicochemical and spectroscopic techniques. AGE formation was assessed by measuring hyperchromicity, early glycation products (ketoamines), carbonyl content, hydroxymethylfurfural (HMF) levels, and fluorescent AGEs. The protective effect of NAC was further evaluated by determining free lysine and arginine contents. Protein aggregation and conformational changes were analyzed using Congo Red binding and fluorescence assays including thioflavin-T and 1-anilinonaphthalene-8-sulfonic acid. NAC significantly inhibited <span>d</span>-ribose-mediated glycation of BSA in a concentration-dependent manner. Treatment with NAC resulted in reduced hyperchromicity, decreased ketoamine formation, and lower carbonyl, HMF, and fluorescent AGE levels. NAC preserved protein integrity by maintaining higher free lysine and arginine contents. In addition, NAC markedly attenuated glycation-induced protein aggregation, as evidenced by reduced Congo Red binding and diminished thioflavin-T and ANS fluorescence, with maximal protection observed at 300 μM. NAC exhibits pronounced anti-glycation and anti-aggregation effects by limiting oxidative stress and glycation-mediated protein modification. These findings demonstrate that NAC effectively attenuates <span>d</span>-ribose-induced glycation and protein aggregation in vitro and provide mechanistic insights into its anti-glycation properties through multiple complementary biochemical mechanisms. Further studies are warranted to evaluate its biological relevance in more complex experimental models.</p>\u0000 </div>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"78 9","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148849332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FOXO6 as a Transcriptional Regulator of Hepatic Metabolic Inflammation and Hepatocarcinogenesis","authors":"Mi Eun Kim,&nbsp;Yukyeong Kim,&nbsp;Jun Sik Lee","doi":"10.1002/iub.70129","DOIUrl":"https://doi.org/10.1002/iub.70129","url":null,"abstract":"<div>\u0000 \u0000 <p>FOXO6 is a member of the FOXO transcription factor family that differs from FOXO1, FOXO3, and FOXO4 in its nucleocytoplasmic regulation, remaining predominantly within the nucleus because it lacks a functional nuclear export sequence. FOXO6 activity can nevertheless be inhibited by insulin/AKT signaling, whereas impaired insulin signaling increases its transcriptional activity in hepatocytes under insulin-resistant and nutrient-rich conditions. Recent studies indicate that FOXO6 regulates hepatic metabolic pathways associated with oxidative injury, inflammatory signaling, and lipid accumulation. In hepatocellular carcinoma, increased FOXO6 expression is associated with glycolytic activity, proliferation, and invasion. We recently reported that FOXO6-dependent transcriptional regulation contributes to reactive oxygen species (ROS) production and inflammasome-associated inflammatory signaling through induction of thioredoxin-interacting protein (TXNIP). Furthermore, FOXO6 regulates lipid metabolic pathways through transcriptional activation of apolipoprotein C3 (ApoC3) and peroxisome proliferator-activated receptor (PPAR) γ together with suppression of PPARα, thereby promoting triglyceride accumulation, mitochondrial dysfunction, and lipotoxic injury in hepatocytes. These metabolic and inflammatory alterations contribute to hepatic steatosis, mitochondrial injury, and inflammatory hepatocellular damage. In hepatocellular carcinoma, increased FOXO6 expression is associated with glycolytic metabolism, angiogenic signaling, proliferative activity, immune suppression, and invasive phenotypes. FOXO6-dependent signaling interacts with STAT3, NF-κB, and β-catenin pathways involved in metabolic adaptation and tumor progression. Recent studies demonstrate relationships between increased FOXO6 expression, vascular invasion, aggressive tumor phenotypes, and reduced survival in hepatocellular carcinoma. This review examines FOXO6-associated transcriptional mechanisms involved in hepatic metabolic inflammation and hepatocarcinogenesis.</p>\u0000 </div>","PeriodicalId":14728,"journal":{"name":"IUBMB Life","volume":"78 9","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148849331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}