Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy最新文献

{"title":"Advances in Mendelian Randomization Studies of Obesity Over the Past Decade: Uncovering Key Genetic Mechanisms.","authors":"Xinyue Lu, Lianhong Ji, Dong Chen, Xiaoyang Lian, Mengqian Yuan","doi":"10.2147/DMSO.S528669","DOIUrl":"10.2147/DMSO.S528669","url":null,"abstract":"<p><p>Obesity is a major global public health issue linked to a wide range of chronic diseases. Understanding its complex causal pathways requires robust analytical methods. Mendelian randomization (MR), which employs genetic variants as instrumental variables, effectively addresses confounding and reverse causation and has become a key tool in obesity research. This review summarizes the development of MR methodologies, from single-sample to multivariable, mediation, and time-series models, and highlights key findings from the past decade. MR studies have revealed causal associations between obesity and nine major disease categories, including cardiovascular, metabolic, cancer, psychiatric, respiratory, renal, reproductive, musculoskeletal, and dermatological disorders. Obesity influences disease risk through mechanisms involving energy metabolism, hormonal regulation, and inflammation, with heterogeneity by age, sex, and fat distribution. Key genes such as <i>MC4R, LEPR, FTO</i>, and <i>FGF21</i> have been identified as potential therapeutic targets. Current challenges include instrument strength, pleiotropy, population stratification, and the external validity of GWAS data. Future research that integrates multi-ancestry GWAS, functional validation, and multi-omics approaches may further enhance the utility of Mendelian randomization. MR provides a robust genetic framework for elucidating obesity's causal effects and informing targeted interventions and personalized treatment strategies.</p>","PeriodicalId":11116,"journal":{"name":"Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy","volume":"18 ","pages":"2399-2415"},"PeriodicalIF":2.8,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12278973/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144682202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Joint Effect of Central Obesity and Family History on Hypertension in Type 2 Diabetes: A Cross-Sectional Study in China.","authors":"Xiangyu Chen, Lijin Chen, Ruying Hu, Weiyuan Yao, Zhimin Ma, Jieming Zhong","doi":"10.2147/DMSO.S536865","DOIUrl":"10.2147/DMSO.S536865","url":null,"abstract":"<p><strong>Purpose: </strong>This study aimed to examine the joint effect of central obesity (CO) and family history of hypertension (FHH) on hypertension in Chinese patients with type 2 diabetes mellitus (T2DM).</p><p><strong>Methods: </strong>A total of 1756 T2DM patients were enrolled from a cross-sectional study conducted in Zhejiang Province, China (March - November 2018). Multivariate logistic regression models were used to analyze factors associated with hypertension and to assess CO-FHH interactions on both additive and multiplicative scales. Associations between waist circumference (WC) and systolic/diastolic blood pressure (SBP/DBP) were evaluated using generalized additive models (GAM) and Spearman correlation. The relationship between WC and hypertension was further explored using restricted cubic splines (RCS).</p><p><strong>Results: </strong>The prevalence of hypertension was 64.52%. WC was positively correlated with SBP (r = 0.25, P<0.001) and DBP (r=0.27, P<0.001), and showed a linear association with hypertension in both sexes (P for non-linearity>0.05). After adjusting for potential covariates, T2DM patients with both CO and FHH had a 4.64-fold higher risk of hypertension (95% CI: 3.22-6.67) compared to the reference group. A statistically significant additive interaction between CO and FHH was observed, with a relative excess risk due to interaction (RERI) of 1.59 (95% CI: 0.39-3.19), an attributable proportion (AP) of 0.34 (95% CI: 0.08-0.51), and a synergy index (SI) of 1.78 (95% CI: 1.13-2.79). No statistically significant multiplicative interaction was found.</p><p><strong>Conclusion: </strong>CO and FHH may jointly contribute to hypertension in Chinese T2DM patients through an additive effect beyond their individual associations. Maintaining a healthy WC is especially important for T2DM patients with a family history of hypertension.</p>","PeriodicalId":11116,"journal":{"name":"Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy","volume":"18 ","pages":"2417-2427"},"PeriodicalIF":2.8,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12278947/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144682203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Research on TCM Comprehensive Treatment of DKD Based on Pathophysiological Mechanism.","authors":"Lei Piao, Jian Ma, Na Zhao, Yongqing Hou, Tehasi Wang","doi":"10.2147/DMSO.S523094","DOIUrl":"10.2147/DMSO.S523094","url":null,"abstract":"<p><p>Diabetic kidney disease (DKD) is the predominant etiology of end-stage renal disease (ESRD). Despite rigorous therapeutic interventions aimed at managing hyperglycemia, regulating blood pressure, and employing renin-angiotensin system inhibitors, the incidence of DKD remains high. Recent investigations have indicated a shift in the disease spectrum of DKD accompanied by significant advancements in the development of novel therapeutic options. Nevertheless, in addition to agents such as renin-angiotensin system inhibitors (RASi), sodium-glucose cotransporter-2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1RA), and mineralocorticoid receptor antagonists (MRA), there is currently no optimal strategy in contemporary medicine to effectively mitigate the progression of DKD. The application of TCM in the management of DKD has demonstrated its potential in delaying disease progression and enhancing patient quality of life, thereby playing a crucial role in the prevention and treatment of this condition. Clinical evidence supports its efficacy and safety profile. This article aimed to explore the TCM approach to DKD, focusing on aspects such as etiology, pathogenesis, syndrome differentiation, and comprehensive treatment, while also analyzing the latest research developments in the pathophysiology of DKD.</p>","PeriodicalId":11116,"journal":{"name":"Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy","volume":"18 ","pages":"2369-2384"},"PeriodicalIF":2.8,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12276746/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144674074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association Between Serum Folic Acid Levels and Type 2 Diabetes Mellitus in Overweight or Obese Patients: A Retrospective Study.","authors":"Yaji Dai, Mingfei Guo, Jianglei Xiong, Lei Jiang","doi":"10.2147/DMSO.S521273","DOIUrl":"10.2147/DMSO.S521273","url":null,"abstract":"<p><strong>Purpose: </strong>The relationship between folic acid (FA) levels and type 2 diabetes mellitus (T2DM) with overweight or obesity remains uncertain. This study aimed to further investigate the relationship between them.</p><p><strong>Methods: </strong>A retrospective study was conducted on 149 patients, comprising 64 patients with T2DM and normal weight and 85 patients with T2DM and overweight or obese status.</p><p><strong>Results: </strong>Our findings revealed significantly lower levels of FA and neutrophil-to-lymphocyte ratio (NLR) in overweight/obese T2DM patients compared to their normal-BMI counterparts (P < 0.001). The overweight/obese cohort exhibited elevated metabolic parameters, including fasting C-peptide, serum uric acid, total cholesterol (TC), triglycerides (TG), and very low-density lipoprotein cholesterol (VLDL-C) levels (P < 0.05). Notably, correlation analysis demonstrated a significant positive association between FA levels and both age (r = 0.341, P < 0.001), diabetes duration (r = 0.278, P = 0.001), and NLR (r = 0.212, P = 0.009). Conversely, inverse correlations were observed between FA levels and C-peptide (r = -0.240, P = 0.004), TG (r = -0.254, P < 0.001), and VLDL-C (r = -0.271, P = 0.001).</p><p><strong>Conclusion: </strong>This research found that FA levels were significantly associated with T2DM in individuals who were overweight or obese.</p>","PeriodicalId":11116,"journal":{"name":"Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy","volume":"18 ","pages":"2361-2367"},"PeriodicalIF":2.8,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12275910/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144674072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Research on the Relationship Between Ectopic Fat and Iron Deposition in the Liver and Pancreas, with Glucose Metabolism in Elderly Obese Patients.","authors":"Hao Nie, Min Liu, Junhong Duan, Hong Liu","doi":"10.2147/DMSO.S518292","DOIUrl":"10.2147/DMSO.S518292","url":null,"abstract":"<p><strong>Purpose: </strong>This study investigates the clinical significance of ectopic fat and iron deposition in the liver and pancreas for glucose metabolism in elderly obese patients, with a focus on their potential for early diabetes screening and intervention.</p><p><strong>Methods: </strong>We conducted a cross-sectional study of 140 elderly obese patients (aged 65-80 years, BMI ≥28 kg/m²) who underwent MRI quantification of hepatic and pancreatic fat (MRI-PDFF) and iron content (R2* values), along with measurements of visceral and subcutaneous fat via T2-weighted imaging. Glucose metabolism was assessed through oral glucose tolerance testing and related biomarkers.</p><p><strong>Results: </strong>Compared to normal glucose tolerance (NGT) and impaired glucose regulation (IGR) groups, elderly obese patients with type 2 diabetes mellitus (T2DM) showed significantly higher ectopic fat in the liver (16.6% vs 6.9-13.4%) and pancreas (13.5% vs 8.5-9.0%), as well as increased visceral fat area (198.0cm² vs 137.8-163.9cm²). Liver fat percentage >11.8% was identified as an independent risk factor for abnormal glucose metabolism (<i>OR</i>=2.05, 95% <i>CI</i> 1.22-3.14), with a 2.05-fold increased risk compared to lower levels. The optimal diagnostic thresholds were determined as 11.8% for liver fat (sensitivity 83.2%, specificity 56.1%; AUC = 0.823) and 6.9% for pancreatic fat (sensitivity 72.2%, specificity 50.2%; AUC = 0.688), highlighting their clinical utility for early risk stratification.</p><p><strong>Conclusion: </strong>Ectopic fat deposition in the liver, particularly when exceeding 11.8%, is a significant independent risk factor for glucose metabolism abnormalities in elderly obese patients. Our findings demonstrate that MRI-based quantification of hepatic fat provides a valuable tool for early identification of diabetes risk, enabling targeted interventions to prevent disease progression. This study highlights the clinical importance of monitoring ectopic fat deposition in clinical practice for elderly obese populations.</p>","PeriodicalId":11116,"journal":{"name":"Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy","volume":"18 ","pages":"2331-2341"},"PeriodicalIF":2.8,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12273728/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144674075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating the Pathogenesis and Treatment of Type 2 Diabetes from the Perspective of Adipose Tissue.","authors":"Zezheng Kang, Zishan Jin, Lei Wu, Aru Sun, Lishuo Dong, Jiarui Li, Qingwei Li, Xiaolin Tong","doi":"10.2147/DMSO.S524000","DOIUrl":"10.2147/DMSO.S524000","url":null,"abstract":"<p><p>Type 2 diabetes mellitus (T2DM) has a high prevalence worldwide; its cardiac, renal, and visual complications greatly affect patients' quality of life. This, together with the large patient base, makes clinical health management of T2DM a problem. Existing studies have shown that obesity and the onset of T2DM are highly correlated, which can start from the earliest lipid metabolism problems and ultimately develop into T2DM. Moreover, adipose tissue can also seriously affect patient treatment by affecting insulin secretion, promoting pancreatic β-cell proliferation, and increasing insulin resistance. Our study describes the association between obesity and T2DM, summarizes the role played by the adipose tissue in T2DM, and focuses on fatty acid esters of hydroxy fatty acids (FAHFA), whose role in improving insulin secretion and increasing insulin sensitivity shows greater potential in T2DM. In addition, we summarize the existing more mature clinical treatment strategies, such as life interventions, drugs, and surgery, which can help control blood glucose levels and reduce adipose-related insulin resistance by reducing the adipose tissue. Among these treatments, Chinese medicine is another factor worth exploring. However, due to the influence of geography, culture, and other factors, this method has only achieved some success in China and part of the East Asia region and has been applied clinically. Although there is no evidence of clinical benefit for obesity or adipose tissue, its clinical benefit for T2DM has been demonstrated; therefore, there is still a need to develop it, as well as considerable potential for development.</p>","PeriodicalId":11116,"journal":{"name":"Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy","volume":"18 ","pages":"2343-2360"},"PeriodicalIF":2.8,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12273715/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144674073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metformin Activation of Sirtuin 3 Signaling Regulates Mitochondrial Function Improves Diabetes-Associated Cognitive Impairment.","authors":"Jiang-Fei An, Hang Su, Chun-Qiang Zhang, Xue-Ting Wang, Guang-Qiong Zhang, Ling-Yun Fu, Yi-Ni Xu, Ling Tao, Xiang-Chun Shen","doi":"10.2147/DMSO.S516173","DOIUrl":"10.2147/DMSO.S516173","url":null,"abstract":"<p><strong>Context: </strong>Diabetes-associated cognitive impairment (DACD) is a prevalent complication of diabetes mellitus, with a strong correlation to both the severity and duration of the disease. While metformin has demonstrated a significant impact on mitigating DACD, the precise mechanisms underlying its therapeutic effects remain inadequately understood.</p><p><strong>Objective: </strong>This study aims to examine the protective effects of metformin (MET) on DACD and to elucidate the underlying mechanisms involved.</p><p><strong>Materials and methods: </strong>C57BL/6J male mice from in vivo animal experiments established DACD by high-fat diet (HFD) for 12 weeks, combined with intraperitoneal injection of low-dose streptozotocin (STZ, 40 mg/kg). Subsequently, DACD mice were administered MET for 2 months. The expression levels of proteins related to mitochondrial function were analyzed using immunohistochemical staining, immunofluorescence double staining, qRT-PCR, and Western blot. Furthermore, the mechanism underlying the improvement of DACD by MET was validated by using the Sirtuin 3 (SIRT3) agonist resveratrol (RES), the inhibitor 3-TYP, and sh-SIRT3 on astrocytes.</p><p><strong>Results: </strong>Our findings indicate that MET significantly ameliorated mitochondrial dysfunction in DACD mice, accompanied by an upregulation of SIRT3 expression. Furthermore, comparable results were noted with the SIRT3 agonist RES. Meanwhile, suppressing SIRT3 expression via sh-SIRT3 or SIRT3 inhibitor 3-TYP in astrocytes largely abolished MET's ability to restore mitochondrial function.</p><p><strong>Conclusion: </strong>It has been demonstrated that MET ameliorates mitochondrial dysfunction by activating the SIRT3 signaling pathway to rescue DACD.</p>","PeriodicalId":11116,"journal":{"name":"Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy","volume":"18 ","pages":"2317-2330"},"PeriodicalIF":2.8,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12266075/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SERUM LncRNA SNHG16: A Biomarker for Diagnosing Childhood Obesity and Predicting Its Progression to Metabolic Syndrome.","authors":"Junjie Hu, Zufen Zheng, Dakang Liang, Yongjin Zhang, Jiejing Chen, Cuiyi Zhou, Chuming You, Qiong Liu","doi":"10.2147/DMSO.S513449","DOIUrl":"10.2147/DMSO.S513449","url":null,"abstract":"<p><strong>Purpose: </strong>Obesity is a major risk factor for metabolic syndrome (MS) in children. This study explores the expression and clinical significance of long non-coding RNA SNHG16 (SNHG16) in childhood obesity and its complications with MS (obesity-MS).</p><p><strong>Patients and methods: </strong>Healthy controls and obese children (categorized as those with simple obesity or obesity-MS) were enrolled. Serum SNHG16 and miR-27a-3p levels were quantified by RT-qPCR. ROC curves evaluated SNHG16's diagnostic value for obesity. Logistic regression analysis identified potential risk factors for the development of obesity-MS. DLR assay and RIP assay confirmed the interaction between SNHG16 and miR-27a-3p. Bioinformatics was used to predict downstream genes of miR-27a-3p and, then GO and KEGG enrichment analysis identified the functions and signaling pathways of these genes.</p><p><strong>Results: </strong>Serum SNHG16 levels were distinctly upregulated in obese children, especially those with obesity-MS. In contrast, miR-27a-3p expression showed the opposite trend. Additionally, SNHG16 was positively correlated with BMI in obese children. Serum SNHG16 exhibited 81.18% sensitivity and 76.47% specificity in distinguishing controls from obese individuals. Furthermore, serum SNHG16, BMI, HOMA-IR, and TG are potential risk factors for MS in obese children. Mechanistically, SNHG16 directly targets miR-27a-3p, and miR-27a-3p targets 65 genes primarily enriched in insulin response and the MAPK, Ras, and mTOR signaling pathways.</p><p><strong>Conclusion: </strong>Elevated serum SNHG16 levels may serve as diagnostic biomarkers for obese children and predict obesity-MS. SNHG16 may also contribute to the progression of obesity and MS by targeting miR-27a-3p.</p>","PeriodicalId":11116,"journal":{"name":"Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy","volume":"18 ","pages":"2305-2316"},"PeriodicalIF":2.8,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12256061/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144625586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fu-Fang-Qi-Di-Hua-Yu-Tang Improves Diabetic Macrovascular Disease via PI3K/AKT Pathway Regulation.","authors":"Shizhao Zhang, Mei Yan, Pengpeng Liang, Ye Zhang, Jiamin Liu, Hai Huang, Guiyun Li, Hongyan Wu","doi":"10.2147/DMSO.S515521","DOIUrl":"10.2147/DMSO.S515521","url":null,"abstract":"<p><strong>Objective: </strong>This study aimed to investigate the active ingredients and mechanisms of Fu-Fang-Qi-Di-Hua-Yu-Tang (FFQD) in alleviating atherosclerosis and insulin resistance in diabetic macrovascular disease (DMD) mice.</p><p><strong>Methods: </strong>Chemical profiling of FFQD was performed using UPLC-Q-TOF-MS. Apoe-/- mice were injected with streptozotocin and fed a high-fat diet to establish DMD. Groups included control (C57BL/6), model (normal saline), low/medium/high-dose FFQD, and western medicine (atorvastatin + metformin). After 12 weeks, aortic morphology, blood glucose/lipid profiles, inflammatory factors, and PI3K/AKT pathway-related targets were analyzed.</p><p><strong>Results: </strong>FFQD contained 159 identified components. Treatment significantly reduced aortic plaque area, blood glucose, lipids, and lowered the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), oxidized low-density lipoprotein (ox-LDL), C-reactive protein (CRP), and monocyte chemoattractant protein-1 (MCP-1). It also reduced nitric oxide synthase 2 (NOS2) level, a marker of macrophage polarization, increased arginase 1 (Arg1) level, regulated macrophage polarization, and improved oxidative stress and inflammatory response. In addition, FFQD activated the receptor for advanced glycation end products (RAGE)/PI3K/AKT/mammalian target of rapamycin (mTOR) pathway in the aorta, inhibited RAGE expression, promoted PI3K, AKT, and mTOR phosphorylation, down-regulated microtubule-associated protein 1A/1B-light chain 3-II/I (LC3 II/I) and nuclear factor κB (NF-κB p65) expression, up-regulated SQSTM1 protein (p62) expression, inhibited excessive autophagy, and reduced vascular endothelial damage caused by long-term high glucose levels. In the liver, FFQD activated the Ras family small molecule G protein (RAP1)/PI3K/AKT/forkhead box protein 01 (FOX01) pathway, inhibited RAP1 expression, promoted PI3K and AKT phosphorylation, suppressed FOX01 expression, and improved insulin resistance.</p><p><strong>Conclusion: </strong>FFQD may improve insulin resistance, regulate glucose and lipid metabolism, inhibit excessive autophagy, induce macrophage polarization, resist inflammation and oxidative stress, inhibit atherosclerosis, and ultimately improve DMD by activating the RAGE/PI3K/AKT/mTOR and RAP1/PI3K/AKT/FOX01 pathways. Therefore, FFQD may be a promising candidate for DMD treatment.</p>","PeriodicalId":11116,"journal":{"name":"Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy","volume":"18 ","pages":"2247-2265"},"PeriodicalIF":2.8,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12255353/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144625584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of Di-(2-Ethylhexyl)-Phthalate on Metabolic Syndrome: Insights from Network Toxicology and Molecular Docking and Dynamics.","authors":"Long Chen, Yu-Li Huang, Fang Liu, Nan Huang, Ding-Cheng Zeng, Yan-Biao Zhong, Jing-Hai Liao, Mao-Yuan Wang","doi":"10.2147/DMSO.S523668","DOIUrl":"10.2147/DMSO.S523668","url":null,"abstract":"<p><strong>Background: </strong>Metabolic syndrome (MetS) is strongly associated with exposure to environmental pollutants, especially endocrine disruptors (EDCs). Di-(2-ethylhexyl)-Phthalate (DEHP), a typical EDC widely found in plastic products, has been shown to interfere with lipid metabolism and insulin signalling. However, the specific molecular mechanism by which it mediates MetS remains unclear.</p><p><strong>Purpose: </strong>This study aimed to systematically investigate the molecular mechanisms underlying the effects of the ubiquitous environmental pollutant DEHP on MetS, thereby providing new insights into the role of environmental toxins in metabolic disorders.</p><p><strong>Methods: </strong>MetS-related disease targets were searched using the GeneCards, OMIM, and TTD databases. DEHP-related targets were obtained from STITCH, SwissTargetPrediction, and ChEMBL. Constructed PPI networks of intersecting targets and visualized and screened core targets in Cytoscape 3.7.1. GO and KEGG pathway analyses were performed using the DAVID database to elucidate biological processes, cellular components, molecular functions, and key pathways (<i>p</i><0.05). In addition, molecular docking and molecular dynamics simulations were used to analyze the interactions between compounds and targets further.</p><p><strong>Results: </strong>150 intersecting targets were identified between DEHP and MetS. The PPI network exhibited core targets, including TP53, ESR1, EGFR, TNF, and IL6. GO analysis showed entries in metabolic processes, transcriptional regulation, and redox reactions. The KEGG pathway showed significant enrichment in AGE-RAGE, FoxO, insulin resistance, and steroid hormone biosynthesis pathways. DEHP showed strong binding affinity to core targets: TP53 (-5.6 kcal/mol), ESR1 (-6.1 kcal/mol), EGFR (-5.4 kcal/mol), and IL6 (-4.8 kcal/mol). Molecular dynamics simulation further verified the results of molecular docking.</p><p><strong>Conclusion: </strong>Our study highlights the interaction between environmental pollutants and metabolic dysfunction. These findings highlight the potential role of DEHP in exacerbating MetS and provide a basis for mitigating its health risks through targeted interventions. Further experimental validation is needed in the future to confirm these mechanistic insights.</p>","PeriodicalId":11116,"journal":{"name":"Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy","volume":"18 ","pages":"2277-2288"},"PeriodicalIF":2.8,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12255270/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144625585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}