Single-Cell Resolution of Cellular Damage Illuminates Disease Progression

Degenerative diseases are marked by the progressive accumulation of cellular damage, leading to impaired cellular function and tissue degeneration. Despite advances in single-cell technologies, capturing the gradual decline of individual cells in vivo remains challenging. Here, we present a novel, universal, cross-model framework for quantifying cellular damage at single-cell resolution, to uncover conserved molecular trajectories of cellular degeneration. This method uses single-cell RNA sequencing data and enables the detection of progressive damage within distinct cell populations under physiological and pathological conditions. We developed the Podocyte Damage Score (PDS) and Hepatocyte Damage Score (HDS) to monitor cellular deterioration in murine models of kidney glomerulosclerosis and liver steatosis, respectively. The application of these scores to both murine and human datasets accurately quantified cellular damage across diverse disease models and distinguished varying degrees of damage even in unperturbed samples. Notably, the PDS revealed circadian gene expression dysregulation as a hallmark of podocyte injury, while the HDS identified a critical threshold of hepatocyte damage leading to cellular senescence and metabolic dysfunction. The approach provides a scalable tool for decoding disease progression and identifying therapeutic targets across degenerative disorders.