Causally Structured Differential Network Modeling for Single-Cell Perturbation Prediction

Cellular perturbation experiments are essential for probing biological mechanisms and guiding therapeutic discovery. While existing methods often treat perturbations as monolithic distributional shifts, they leave the underlying structural variations implicit. Rather than attempting to infer independent global networks for every condition, we propose scPertCRL, a causally structured generative framework for single-cell perturbation prediction. scPertCRL decomposes perturbation effects into a shared latent structural backbone, condition-specific structural modulations, and exogenous shifts. By leveraging biologically informed embeddings and mechanism-aware supervision, Differential Network Learner parameterizes these localized structural changes, enabling robust generalization to unseen interventions. Extensive experiments on genetic and pharmacological benchmarks demonstrate that scPertCRL significantly improves predictive accuracy and out-of-distribution generalization, while yielding model-based insights into perturbation mechanisms.