Prediction of cellular morphology changes under perturbations with a transcriptome-guided diffusion model

Investigating cell morphology changes after perturbations using high-throughput image-based profiling is increasingly important for phenotypic drug discovery, including predicting mechanisms of action (MOA) and compound bioactivity. The vast space of chemical and genetic perturbations makes it impractical to explore all possibilities using conventional methods. Here we propose MorphDiff, a transcriptome-guided latent diffusion model that simulates high-fidelity cell morphological responses to perturbations. We demonstrate MorphDiff’s effectiveness on three large-scale datasets, including two drug perturbation and one genetic perturbation dataset, covering thousands of perturbations. Extensive benchmarking shows MorphDiff accurately predicts cell morphological changes under unseen perturbations. Additionally, MorphDiff enhances MOA retrieval, achieving an accuracy comparable to ground-truth morphology and outperforming baseline methods by 16.9% and 8.0%, respectively. This work highlights MorphDiff’s potential to accelerate phenotypic screening and improve MOA identification, making it a powerful tool in drug discovery.