Single-cell transcriptomics reveals apolipoprotein A4-mediated metabolic-immune reprogramming in lymphocytes during early obesity-related chronic kidney disease

• Apoa4 knockout exacerbates insulin resistance and renal lipid accumulation in high-fat diet-induced obese mice, highlighting its protective role in early obesity-related CKD. • Single-cell RNA sequencing reveals that Apoa4 deletion remodels the renal immune-metabolic landscape, compromising T, NK, and B cell functions while expanding cytotoxic Gzma+ NK cells and Derl3+ plasma cells. • Mechanistically, Apoa4 deletion disrupts key transcription factor networks (Lef1, Runx3, Irf8, T-bet, Eomes, Tcf4, Lmo2, Xbp1) and downregulates effector genes (Ifng, Il1b), leading to metabolic dysregulation and oxidative stress. • CellChat analysis predicts altered intercellular signaling (IFN-II, IL-1, FASLG, ENHO, ANGPTL, IL-2), providing a comprehensive resource for therapeutic targeting of Apoa4-mediated pathways in obesity-related CKD.