Frontiers in endocrinology · 2026
A novel continuous-progression CKM model combined with multi-omics data integration identifies lipid metabolic drivers of disease progression.
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Ye Hai-Lun, Wang Ya-Ni, Li Gang-Ao, Jin Xing-Hui, Li Yang, Jin Ying-Hua
Аннотация
INTRODUCTION: Cardiovascular-kidney-metabolic (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.
METHODS: 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.
RESULTS: 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. PPARγ, 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 PPARγ/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.
DISCUSSION: Collectively, this study establishes a translational CKM model and highlights renal lipotoxic remodeling as a potential therapeutic target in CKM progression.
METHODS: 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.
RESULTS: 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. PPARγ, 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 PPARγ/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.
DISCUSSION: Collectively, this study establishes a translational CKM model and highlights renal lipotoxic remodeling as a potential therapeutic target in CKM progression.