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Orthogonal projection to latent structures-discriminant analysis (OPLS-DA) was applied to identify significant metabolic perturbations, while bidirectional O2PLS integration elucidated metabolic-transcriptomic correlations. Lipid reaction networks were reconstructed using LINEX2, followed by local topology exploration to identify highly interconnected modules. Mechanistic pathways governing gene-metabolite-lipid interactions were inferred via random walk with restart algorithms and validated by gene set enrichment analysis (GSEA).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec sec-type=\"results\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Transcriptomics revealed extensive dysregulation of metabolic and lipid regulatory pathways in db\/db. Metabolomic integration pinpointed perturbations within glycine-serine-threonine (Gly-Ser-Thr) metabolism as the most significantly perturbed pathway (P\u202f&lt;\u202f0.001), with cross-omics validation identifying GLUL as a pivotal regulatory gene through. Lipidomics uncovered pronounced abnormalities in cardiolipin species composition and plasmalogen profiles. Transcriptome-lipidome integration demonstrated impaired phosphatidylcholine (PC) biosynthesis, mechanistically linked to dysregulation of choline phosphotransferase 1 (\n                      <jats:italic toggle=\"yes\">chpt1<\/jats:italic>\n                      ), which correlated significantly with compromised tissue regeneration capacity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec sec-type=\"conclusion\">\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This multi-omics study systematically delineates the molecular landscape of DN pathogenesis, uncovering previously underappreciated metabolic perturbations and distinct lipid dysregulation patterns. Our findings elucidate mechanistic insights into extra-glycemic disease drivers and propose potential therapeutic targets for DN management.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1016\/j.csbj.2025.07.037","type":"journal-article","created":{"date-parts":[[2025,7,23]],"date-time":"2025-07-23T15:16:12Z","timestamp":1753283772000},"page":"3399-3409","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":6,"title":["Multi-omics characterization of diabetic nephropathy in the db\/db mouse model of type 2 diabetes"],"prefix":"10.34133","volume":"27","author":[{"given":"Liping","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Jing'an District Central Hospital of Shanghai, Fudan University, Shanghai, China & National Clinical Research Center for Eye Diseases, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, 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