Cell-type-specific damage scores reveal kidney and liver disease trajectories in single-cell and spatial transcriptomics.

Degenerative diseases progress through gradual cell-intrinsic damage that is difficult to resolve with bulk transcriptomics or discrete cell-state analysis. We introduce a generalizable single-cell and spatial transcriptomics framework that quantifies continuous damage trajectories in vivo using cell-type-specific scores. Applied to chronic kidney disease and metabolic dysfunction-associated steatotic liver disease, the podocyte damage score (PDS) and hepatocyte damage score (HDS) place individual podocytes and hepatocytes on a health-to-damage axis. Across mouse and human single-cell RNA sequencing (scRNA-seq), single-nucleus RNA-seq (snRNA-seq), spatial transcriptomics, proteomics, histology, and clinical datasets, PDS and HDS robustly detect disease-associated damage, align disease models as well as unperturbed cells, and reveal conserved pathways. The PDS links podocyte injury and FSGS progression to circadian gene-expression disruption. The HDS identifies a damage threshold in metabolic dysfunction-associated steatotic liver disease (MASLD)/NASH beyond which hepatocytes adopt senescent, metabolically dysfunctional states. These damage scores enable scalable mapping of degenerative disease progression and stage-specific therapeutic targets.