# Generalizable single-cell perturbation response prediction using energy-guided flow matching

arXiv: https://arxiv.org/abs/2610.02232 · HTML: https://mlsanity.com/paper/2610.02232/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Placed in Flow matching, time series and science, one of 14 directions in Diffusion models.
- Builds on 9 of its 37 references that are in the map.
- First posted on arXiv 27 Sep 2026.

## Placed in

- Diffusion models / [Flow matching, time series and science](https://mlsanity.com/diffusion/flow-matching-time-series-and-science/)

## Builds on (most cited first, 9 of 9)

- [PyTorch: An Imperative Style, High-Performance Deep Learning Library](https://mlsanity.com/paper/1912.01703/) (2019)
- [Flow Matching for Generative Modeling](https://mlsanity.com/paper/2210.02747/) (2022)
- [Sinkhorn Distances: Lightspeed Computation of Optimal Transportation Distances](https://mlsanity.com/paper/1306.0895/) (2013)
- [Improving and generalizing flow-based generative models with minibatch optimal transport](https://mlsanity.com/paper/2302.00482/) (2023)
- [Your Classifier is Secretly an Energy Based Model and You Should Treat it Like One](https://mlsanity.com/paper/1912.03263/) (2019)
- [TrajectoryNet: A Dynamic Optimal Transport Network for Modeling Cellular Dynamics](https://mlsanity.com/paper/2002.04461/) (2020)
- [Predicting Cellular Responses to Novel Drug Perturbations at a Single-Cell Resolution](https://mlsanity.com/paper/2204.13545/) (2022)
- [scDFM: Distributional Flow Matching Model for Robust Single-Cell Perturbation Prediction](https://mlsanity.com/paper/2602.07103/) (2026)
- [SwAMP: Swapped Assignment of Multi-Modal Pairs for Cross-Modal Retrieval](https://mlsanity.com/paper/2111.05814/) (2021)

## Abstract (arXiv)

Predicting phenotypic and transcriptional responses to perturbations at single-cell resolution provides a powerful tool for probing biological systems. However, existing methods typically rely on fixed mappings learned during training, making it challenging to calibrate distribution shifts or adapt to novel perturbation conditions during inference. Here, we present scEGFlow, an energy-guided flow matching framework that dynamically bridges control and perturbed cellular states. scEGFlow models continuous transitions from control cell populations to perturbed states using conditional flow matching. It then applies condition-specific energy gradients to correct and steer these predictions, enabling flexible adjustments without retraining the flow model. Evaluations across benchmarks spanning imaging phenotypes and transcriptomic profiles show that scEGFlow outperforms existing methods in reconstructing response distributions under both seen and unseen perturbation conditions, faithfully preserving cellular manifold geometry and population heterogeneity. This advantage is notable when adapting to new conditions with only a few measured cells, consistently improving prediction accuracy. Furthermore, scEGFlow accurately recapitulates perturbation-induced up- and down-regulation patterns across consensus gene expression signatures, where energy guidance improves the agreement between predicted and observed regulatory directions. Ultimately, these findings demonstrate that scEGFlow provides a modular, generalizable, and steerable solution for single-cell perturbation modeling. By grounding generative flows in learned biological landscapes, this architecture establishes a new computational paradigm for navigating and manipulating cellular behavior in silico.