{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T02:20:49Z","timestamp":1793413249475,"version":"4.5.0"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Cardiovascular\u2013kidney\u2013metabolic (CKM) syndrome represents an emerging systemic disorder characterized by intertwined metabolic dysfunction, chronic kidney disease, and cardiovascular injury, yet robust preclinical models and mechanistic insights remain limited.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Here, we established a progressive rat model of CKM syndrome by combining high-fat\/high-sucrose exposure with adenine-induced renal stress, capturing temporal changes from early metabolic dysregulation to advanced multi-organ injury. Integrative multi-omics analyses incorporating network toxicology, single-cell RNA sequencing, and spatial transcriptomics were performed to investigate molecular features associated with CKM progression. Finally, AI-assisted virtual screening coupled with molecular docking was conducted to identify potential multi-target therapeutic candidates.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Longitudinal phenotyping revealed a temporal pattern in which early metabolic abnormalities preceded more prominent renal and cardiovascular impairment. Integrative multi-omics analyses incorporating network toxicology, single-cell RNA sequencing, and spatial transcriptomics consistently converged on lipid metabolic dysregulation as a prominent molecular feature associated with CKM progression. PPAR\u03b3, ESR1, and FASN were identified as candidate regulatory nodes associated with CKM-related lipid remodeling. Single-cell analyses revealed enrichment of lipid metabolic programs in renal epithelial compartments, particularly proximal tubular cells, suggesting their potential involvement in CKM-associated renal metabolic remodeling. Spatial transcriptomics further revealed patterns consistent with ectopic adipocyte infiltration, lipid-associated niche remodeling, increased PPAR\u03b3\/FASN expression, and reduced ESR1 expression in diseased kidneys. AI-assisted virtual screening coupled with molecular docking identified BRD-K26818574 as a potential multi-target therapeutic candidate.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Collectively, this study establishes a translational CKM model and highlights renal lipotoxic remodeling as a potential therapeutic target in CKM progression.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2026.1910505","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T04:35:23Z","timestamp":1785299723000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["A novel continuous-progression CKM model combined with multi-omics data integration identifies lipid metabolic drivers of disease progression"],"prefix":"10.3389","volume":"17","author":[{"given":"Hai-Lun","family":"Ye","sequence":"first","affiliation":[{"name":"Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, School of Life Sciences, Jilin University","place":["Changchun, China"]},{"name":"Laboratory of Ginseng and Human Health, Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya-Ni","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, School of Life Sciences, Jilin University","place":["Changchun, China"]},{"name":"Laboratory of Ginseng and Human Health, Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang-Ao","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, School of Life Sciences, Jilin University","place":["Changchun, China"]},{"name":"Laboratory of Ginseng and Human Health, Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xing-Hui","family":"Jin","sequence":"additional","affiliation":[{"name":"Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, School of Life Sciences, Jilin University","place":["Changchun, China"]},{"name":"Laboratory of Ginseng and Human Health, Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, School of Life Sciences, Jilin University","place":["Changchun, China"]},{"name":"Laboratory of Ginseng and Human Health, Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying-Hua","family":"Jin","sequence":"additional","affiliation":[{"name":"Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, School of Life Sciences, Jilin University","place":["Changchun, China"]},{"name":"Laboratory of Ginseng and Human Health, Jilin University","place":["Changchun, China"]},{"name":"Ginseng Research Institute, Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-018-0119-4","article-title":"Epidemiology of cardiovascular disease in China: current features and implications","volume":"16","author":"Zhao","year":"2019","journal-title":"Nat Rev Cardiol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1518295","article-title":"Associations of prognostic nutritional index with cardiovascular all-cause mortality among CVD patients with diabetes or prediabetes: evidence from the NHANES 2005-2018","volume":"16","author":"Xu","year":"2025","journal-title":"Front Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2023.10.018","article-title":"KDIGO 2024 clinical practice guideline for the evaluation and management of chronic kidney disease","volume":"105","author":"Stevens","year":"2024","journal-title":"Kidney Int"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00908.2024","article-title":"Endothelial dysfunction in chronic kidney disease: a clinical perspective","volume":"329","author":"Cho","year":"2025","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-019-0176-8","article-title":"Obesity: global epidemiology and pathogenesis","volume":"15","author":"Blueher","year":"2019","journal-title":"Nat Rev Endocrinol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.5005\/jp\/books\/10808_4","article-title":"Type 2 diabetes","volume":"389","author":"Chatterjee","year":"2017","journal-title":"Lancet"},{"key":"B7","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1038\/nrendo.2017.151","article-title":"Global aetiology and epidemiology of type 2 diabetes mellitus and its complications","volume":"14","author":"Zheng","year":"2018","journal-title":"Nat Rev Endocrinol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1186\/s12933-026-03148-6","article-title":"Associations of triglyceride-glucose-related composite obesity indices with cardiovascular diseases and mortality: a systematic review and meta-analysis","volume":"25","author":"Liu","year":"2026","journal-title":"Cardiovasc Diabetol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvag007","article-title":"Impact of amino acid supplementation on cardiovascular and chronic kidney diseases: a systematic review","volume":"122","author":"Mikolajetz","year":"2026","journal-title":"Cardiovasc Res"},{"key":"B10","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1038\/s41387-026-00412-2","article-title":"The association between steatotic liver disease and chronic kidney disease: a meta-analysis and Mendelian randomization study highlighting metabolic comorbidities","volume":"16","author":"Ji","year":"2026","journal-title":"Nutr Diabetes"},{"key":"B11","doi-asserted-by":"publisher","first-page":"E984","DOI":"10.1161\/cir.0000000000000973","article-title":"Obesity and cardiovascular disease: a scientific statement from the American Heart Association","volume":"143","author":"Powell-Wiley","year":"2021","journal-title":"Circulation"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1882","DOI":"10.3390\/ijms25031882","article-title":"The role of obesity in type 2 diabetes mellitus-an overview","volume":"25","author":"Chandrasekaran","year":"2024","journal-title":"Int J Mol Sci"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.2337\/dc25-s008","article-title":"8. Obesity and weight management for the prevention and treatment of type 2 diabetes: standards of care in diabetes-2025","volume":"48","year":"2025","journal-title":"Diabetes Care"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1161\/cir.0000000000001186","article-title":"A synopsis of the evidence for the science and clinical management of cardiovascular-kidney-metabolic (CKM) syndrome: a scientific statement from the American Heart Association","volume":"148","author":"Ndumele","year":"2023","journal-title":"Circulation"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.cpcardiol.2023.102344","article-title":"Cardiovascular-kidney-metabolic (CKM) syndrome: a state-of-the-art review","volume":"49","author":"Sebastian","year":"2024","journal-title":"Curr Prob Cardiol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1186\/s12933-025-02692-x","article-title":"Joint association of estimated glucose disposal rate and systemic inflammation response index with mortality in cardiovascular-kidney-metabolic syndrome stage 0-3: a nationwide prospective cohort study","volume":"24","author":"Chen","year":"2025","journal-title":"Cardiovasc Diabetol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"19151","DOI":"10.1038\/s41598-024-69819-0","article-title":"Association between systemic immune-inflammation index and cardiovascular-kidney-metabolic syndrome","volume":"14","author":"Gao","year":"2024","journal-title":"Sci Rep"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1002\/oby.24356","article-title":"Cardiovascular indexes and oxidative balance in advanced cardiovascular-kidney-metabolic syndrome","volume":"33","author":"Yan","year":"2025","journal-title":"Obesity"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3389\/fnut.2025.1597693","article-title":"The role of oxidative balance score in cardiovascular-kidney-metabolic syndrome progression and mortality: insights from NHANES 1999-2020","volume":"12","author":"Xie","year":"2025","journal-title":"Front Nutr"},{"key":"B20","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1007\/s12020-026-04593-9","article-title":"Aldosterone fuels the progression of cardiovascular-kidney -metabolic syndrome: focus on primary aldosteronism spectrum","volume":"91","author":"Wei","year":"2026","journal-title":"Endocrine"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3390\/jcm14082833","article-title":"Cardiovascular-kidney-metabolic syndrome: a new paradigm in clinical medicine or going back to basics","volume":"14","author":"Mutruc","year":"2025","journal-title":"J Clin Med"},{"key":"B22","doi-asserted-by":"publisher","first-page":"i3","DOI":"10.1093\/ndt\/gfae212","article-title":"Combination therapy: an upcoming paradigm to improve kidney and cardiovascular outcomes in chronic kidney disease","volume":"40","author":"Alicic","year":"2025","journal-title":"Nephrol Dialysis Transplant"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3390\/biom15020213","article-title":"From cardiovascular-kidney-metabolic syndrome to cardiovascular-renal-hepatic-metabolic syndrome: proposing an expanded framework","volume":"15","author":"Theodorakis","year":"2025","journal-title":"Biomolecules"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1126\/science.adi8577","article-title":"Active learning framework leveraging transcriptomics identifies modulators of disease phenotypes","volume":"390","author":"DeMeo","year":"2025","journal-title":"Science"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/s41684-024-01457-5","article-title":"A novel model of cardiovascular-kidney-metabolic syndrome combining unilateral nephrectomy and high-salt-sugar-fat diet in mice","volume":"53","author":"Carvalho","year":"2024","journal-title":"Lab Anim"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.83263","article-title":"Improvement of kidney function following unilateral nephrectomy in a patient with cardiovascular-kidney-metabolic (CKM) syndrome","volume":"17","author":"Asopa","year":"2025","journal-title":"Cureus"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1186\/s12944-025-02759-4","article-title":"Interactions between lipid droplets and mitochondria in metabolic diseases","volume":"24","author":"Wang","year":"2025","journal-title":"Lipids Health Dis"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2022.09.020","article-title":"Mitochondrial alterations in fatty liver diseases","volume":"78","author":"Fromenty","year":"2023","journal-title":"J Hepatol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1038\/s41581-025-00938-1","article-title":"Endoplasmic reticulum stress as a driver and therapeutic target for kidney disease","volume":"21","author":"Byun","year":"2025","journal-title":"Nat Rev Nephrol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.plipres.2022.101198","article-title":"Endoplasmic reticulum stress and lipids in health and diseases","volume":"89","author":"Celik","year":"2023","journal-title":"Prog Lipid Res"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2023.102643","article-title":"Mitochondrial cholesterol: metabolism and impact on redox biology and disease","volume":"61","author":"Goicoechea","year":"2023","journal-title":"Redox Biol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2021.111315","article-title":"Adipose tissue and insulin resistance in obese","volume":"137","author":"Ahmed","year":"2021","journal-title":"Biomed Pharmacotherapy"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2017.09.033","article-title":"Renal tubule injury: a driving force toward chronic kidney disease","volume":"93","author":"Liu","year":"2018","journal-title":"Kidney Int"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines12061191","article-title":"Anemia of chronic kidney disease-a narrative review of its pathophysiology, diagnosis, and management","volume":"12","author":"Badura","year":"2024","journal-title":"Biomedicines"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1161\/hypertensionaha.122.20824","article-title":"Intrarenal renin-angiotensin system activation alters relationship between systolic blood pressure and progression of chronic kidney disease","volume":"80","author":"Park","year":"2023","journal-title":"Hypertension"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3390\/life14010013","article-title":"Chronic kidney disease interplay with comorbidities and carbohydrate metabolism: a review","volume":"14","author":"Kushwaha","year":"2024","journal-title":"Life-Basel"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/nrneph.2012.191","article-title":"The role of the kidney in regulating arterial blood pressure","volume":"8","author":"Wadei","year":"2012","journal-title":"Nat Rev Nephrol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3390\/antiox9080752","article-title":"Chronic kidney disease as oxidative stress- and inflammatory-mediated cardiovascular disease","volume":"9","author":"Podkowinska","year":"2020","journal-title":"Antioxidants"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2017.7066","article-title":"Lipid deposition in kidney diseases: interplay among redox, lipid mediators, and renal impairment","volume":"28","author":"Su","year":"2018","journal-title":"Antioxidants Redox Signaling"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1549484","article-title":"Targeting lipid metabolic reprogramming to alleviate diabetic kidney disease: molecular insights and therapeutic strategies","volume":"16","author":"Wei","year":"2025","journal-title":"Front Immunol"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1910505\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T04:35:29Z","timestamp":1785299729000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1910505\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,29]]},"references-count":40,"alternative-id":["10.3389\/fendo.2026.1910505"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2026.1910505","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,29]]},"article-number":"1910505"}}