Abstract
Dissecting cell-state-specific changes in gene regulation induced by perturbations is crucial for understanding biological mechanisms. However, single-cell sequencing provides only unmatched snapshots of cells under different conditions. This destructive measurement process hinders the estimation of individualized treatment effects (ITEs), which are essential for pinpointing these heterogeneous mechanistic responses. We develop scDRP, a generative framework that leverages disentangled representation learning with asymptotic correctness guarantees to separate perturbation-dependent and perturbation-independent latent variables via a sparsity regularized β -VAE. Assuming quantile-preserving effects of perturbations conditional on confounders, scDRP performs conditional optimal transport in the latent space to infer counterfactual states and estimate ITEs. Applied to simulated and real single-cell perturbation data, scDRP accurately estimates treatment effects and individual counterfactual responses, revealing cell type-specific functional gene module dynamics. Specifically, it captures distinct cellular patterns under rhinovirus and cigarette-smoke extract exposures, reveals heterogeneous responses to interferon stimulation across diverse immune cell types, and identifies distinct functional module activation in chronic myeloid leukemia cells following CRISPR knockouts targeting different genes. scDRP also generalizes to unseen perturbation doses and combinations. Our framework provides a principled computational approach to extracting heterogeneous causal relationships from single-cell perturbation data, enabling a deeper understanding of cellular and molecular mechanisms.