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

• • Apoa4 deletion in DIO mice exacerbated insulin resistance and renal lipid accumulation, with scRNA-seq revealing compromised T, NK, and B cell immune functions despite expanded Gzma+ NK and Derl3+ plasma cell populations. This indicates Apoa4 as a homeostatic regulator; its loss may accelerate CKD progression, highlighting a therapeutic target for obesity-related renal injury. • • Mechanistically, Apoa4 deficiency aggravated metabolic dysregulation and oxidative stress, downregulating Ifng and Il1b expression. This suppression of key effector genes suggests that Apoa4 maintains pro-inflammatory and metabolic signaling necessary for immune competence, and its absence may impair pathogen defense and tissue repair in early CKD. • • Transcription factor network perturbations were observed: Lef1 and Runx3 in Cd8+ T cells; Irf8, T-bet, and Eomes in NK cells; and Tcf4, Lmo2, and Xbp1 in B cells. These disruptions indicate that Apoa4 influences lineage-specific transcriptional programs, potentially altering immune cell differentiation and function, which could serve as biomarkers for early CKD diagnosis. • • CellChat predicted disrupted IFN-II, IL-1, FASLG, ENHO, and ANGPTL signaling, alongside enhanced IL-2-mediated suppression. This signaling rewiring suggests that Apoa4 loss creates an immunosuppressive microenvironment, which may contribute to CKD progression and offers potential targets for immunomodulatory therapies in obesity-related kidney disease.