Integrated Bulk Transcriptomic and Single-Cell Analyses Reveal Extracellular-Matrix Remodeling and Tubular Metabolic Failure in ADPKD Progression

Background: Autosomal dominant polycystic kidney disease (ADPKD) progression involves cyst expansion, interstitial remodeling, and progressive loss of renal function, but the cell-type-resolved programs linking cyst burden to tissue remodeling remain incompletely defined. Methods: We integrated the cyst-size-stratified human bulk transcriptomic dataset GSE7869 with the time-resolved Pkd1 single-cell dataset GSE268494. Differentially expressed genes were identified across small-, middle- and large-cyst groups, modeled by Mfuzz temporal clustering, prioritized by protein–protein interaction topology and functional enrichment, and further evaluated by immune deconvolution, single-cell mapping, AUCell pathway scoring and CellPhoneDB ligand–receptor inference. Results: We identified 3842 shared differentially expressed genes and two dominant monotonic modules. The progressively upregulated module was enriched for extracellular-matrix organization, adhesion, and fibrosis-associated genes, including COL1A1, COL5A2, FBN1, BGN, LAMC1, HSPG2, MMP2, LOX, and ITGA5. The progressively downregulated module highlighted tubular transport, proton transport, and mitochondrial/metabolic genes, including SLC12A3, AQP2, ATP5A1, ATP6V0C, ATP6V1B1, NDUFV1, REN, and AGT. Single-cell analyses localized the matrix module mainly to fibroblast/stromal compartments and the transport/metabolic module to segment-specific tubular epithelial populations. Immune deconvolution and ligand–receptor inference further implicated macrophage-associated remodeling and TGFB1-, CD47-, CD200-, PECAM1- and TNF-superfamily-related immune-parenchymal communication. Conclusions: ADPKD progression is associated with coordinated ECM/immune remodeling and tubular metabolic failure, providing candidate markers and communication axes for future spatial and functional validation.