This project explores the metabolic mechanisms linking mitochondrial dysfunction to redox imbalance during the progression of renal fibrosis in Chronic Renal Failure (CRF). Using an integrated multi-omics approach, we performed TMT-based quantitative proteomics and LC-MS/MS untargeted metabolomics on fibrotic renal tissues to map the molecular landscape of fibrogenesis. Our data reveals a significant remodeling of mitochondrial oxidative phosphorylation (OXPHOS) components alongside the downregulation of critical NADPH-generating enzymes, specifically ME1, ME2, and IDH1. These proteomic shifts correlate with metabolomic evidence of decreased NADPH availability and a disrupted glutathione redox system (GSH/GSSG). Furthermore, we identified the suppression of NRF2-dependent antioxidant defenses, including HO-1 and GPX4, which drives excessive oxidative stress and extracellular matrix accumulation. The study further validates these findings through in vitro experiments, demonstrating that restoring redox homeostasis with N-acetylcysteine (NAC) or Mito-TEMPO alleviates TGF-β1-induced fibroblast activation. This dataset provides comprehensive evidence that the coordinated disruption of mitochondrial OXPHOS and NADPH metabolism is a central driver of renal fibrosis. By archiving these proteomic and metabolomic profiles, we provide a valuable resource for identifying therapeutic targets focused on mitochondrial redox metabolism to mitigate the global burden of chronic kidney disease and fibrotic progression.