Multi-Organ Multi-Omics Reveals Ferroptosis-Associated Signatures and Metabolic Reprogramming in Unilateral Nephrectomy and Pro-Inflammatory Diet-Induced Cardiovascular–Kidney–Metabolic Syndrome

Background/Objectives: Cardiovascular–kidney–metabolic (CKM) syndrome is a recently defined systemic disorder linking metabolic dysfunction with cardiovascular and renal disease. Clinical evidence suggests that pro-inflammatory dietary patterns are associated with adverse CKM outcomes, yet the underlying mechanisms remain poorly understood. This study aimed to investigate whether a pro-inflammatory diet drives CKM pathogenesis and to delineate the molecular networks across multiple organs using an integrative multi-omics approach in a preclinical mouse model. Methods: A CKM mouse model was established via unilateral nephrectomy combined with a high-fat/high-sugar/high-salt diet for 20 weeks. Untargeted plasma metabolomics (n = 6) and DIA-based plasma proteomics (n = 3) were performed. In addition, transcriptomic and proteomic profiling of heart, kidney, and adipose tissue were conducted (n = 3). Histopathological examination, echocardiography, and metabolic measurements were used to assess cardiorenal and metabolic phenotypes. Multi-omics integration was performed to identify shared pathways and mechanistic networks. Results: CKM mice developed marked hypertension, hyperglycaemia, increased adiposity, cardiac and renal fibrosis, and significantly reduced cardiac function. Plasma metabolomics revealed upregulation of acylcarnitines, lysophospholipids, and bile acids, with KEGG enrichment indicating ferroptosis-related pathways. α-Tocopherol (vitamin E) was significantly elevated, suggesting a compensatory antioxidant response. Multi-organ transcriptomic and proteomic analyses uncovered organ-specific yet interconnected molecular signatures: the heart showed lipid metabolic reprogramming, oxidative stress, and fibrotic remodeling; the kidney exhibited inflammation, epithelial-to-mesenchymal transition, and fibrosis; and adipose tissue displayed lipid metabolic dysregulation and pronounced inflammatory activation. Integrated analysis converged on shared pathways involving metabolic reprogramming, oxidative stress/ferroptosis, inflammatory activation, and extracellular matrix remodeling, which were linked to multi-organ damage. Conclusions: A pro-inflammatory diet is associated with CKM pathophysiology, characterized by metabolic reprogramming and tissue-level lipid peroxidation with 4-Hydroxynonenal (4-HNE) accumulation. Acylcarnitines, lysophospholipids, and bile acids are candidate biomarkers, and ferroptosis-related pathways are implicated as therapeutic targets, pending functional validation, in CKM progression. The multi-organ multi-omics atlas provides a translational framework for mechanism-guided therapeutic strategies in CKM syndrome.