A diet rich in saturated fat and carbohydrates causes a low-grade chronic inflammation in several organs including nonalcoholic steatohepatitis. The environment-driven lipotocicity and glucotoxicity induce tissue damage, which promotes dendritic cell adjuvanticity, and supports an MHC-class-II immunopeptidome enriched in peptides derived from proteins involved in cellular metabolism, oxidative phosphorylation and molecular cellular responses to oxidative stress. To investigate the impact of metabolic syndrome on the whole cellular proteome of antigen presenting cells (APCs) we isolated six biological replicates consisted of total proteomic extracts DCs lysates from B6 mice on normal and high fructose/high fat (HFHF) diet and employed a quantitative label-free data independent (DIA) nanoLC-MS/MS analysis of redox stress mediated changes in the protein expression profiles in HFHF vs normal diet. The LFQ DIA analysis of cellular proteomics changes induced by HFHF diet in the DCs highlighted the involvement of proteins associated with cellular pathways involved in lipid and carbohydrate metabolism, oxidative phosphorylation, cell death and inflammation. Altogether depicting an image of cells under metabolic and oxidative stress with up-regulated inflammatory pathways.