# PerturbCellRL: Aligning Distributions and Grounding Biology via Post-Training Perturbation Generators

arXiv: https://arxiv.org/abs/2606.27752 · HTML: https://mlsanity.com/paper/2606.27752/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 15 of its 35 references that are in the map.
- First posted on arXiv 26 Jun 2026.

## Builds on (most cited first, 15 of 15)

- [Flow Matching for Generative Modeling](https://mlsanity.com/paper/2210.02747/) (2022)
- [Flow Straight and Fast: Learning to Generate and Transfer Data with Rectified Flow](https://mlsanity.com/paper/2209.03003/) (2022)
- [Training Diffusion Models with Reinforcement Learning](https://mlsanity.com/paper/2305.13301/) (2023)
- [Flow-GRPO: Training Flow Matching Models via Online RL](https://mlsanity.com/paper/2505.05470/) (2025)
- [DPOK: Reinforcement Learning for Fine-tuning Text-to-Image Diffusion Models](https://mlsanity.com/paper/2305.16381/) (2023)
- [DanceGRPO: Unleashing GRPO on Visual Generation](https://mlsanity.com/paper/2505.07818/) (2025)
- [Flow Matching Guide and Code](https://mlsanity.com/paper/2412.06264/) (2024)
- [DiffusionNFT: Online Diffusion Reinforcement with Forward Process](https://mlsanity.com/paper/2509.16117/) (2025)
- [MixGRPO: Unlocking Flow-based GRPO Efficiency with Mixed ODE-SDE](https://mlsanity.com/paper/2507.21802/) (2025)
- [The Cramer Distance as a Solution to Biased Wasserstein Gradients](https://mlsanity.com/paper/1705.10743/) (2017)
- [How to Build the Virtual Cell with Artificial Intelligence: Priorities and Opportunities](https://mlsanity.com/paper/2409.11654/) (2024)
- [Modelling Cellular Perturbations with the Sparse Additive Mechanism Shift Variational Autoencoder](https://mlsanity.com/paper/2311.02794/) (2023)
- [CellFlux: Simulating Cellular Morphology Changes via Flow Matching](https://mlsanity.com/paper/2502.09775/) (2025)
- [scDFM: Distributional Flow Matching Model for Robust Single-Cell Perturbation Prediction](https://mlsanity.com/paper/2602.07103/) (2026)
- [CellFluxRL: Biologically-Constrained Virtual Cell Modeling via Reinforcement Learning](https://mlsanity.com/paper/2603.21743/) (2026)

## Abstract (arXiv)

Single-cell perturbation models can reduce costly wet-lab screening by predicting how cells respond transcriptionally to interventions. Recent advances in flow-matching have enabled population-level prediction of cellular responses. However, flow-matching training can fail to recover certain target distributions even within the model family, limiting its ability to capture cellular heterogeneity. We first prove that post-training can recover these distributions, then introduce PerturbCellRL, a reinforcement learning framework that post-trains single-cell perturbation generators using per-cell rewards. The central component is a gene-expression energy witness that translates population-level discrepancies into per-cell feedback. We further prove that this reward's policy gradient points toward better distributional alignment. Two complementary rewards, calibrated on real cells, penalize atypical expression profiles and insufficient pathway-level responses to perturbations. Across genetic and chemical perturbation benchmarks, PerturbCellRL substantially improves distributional alignment and recovers pathway enrichment patterns more faithfully. These results establish reward-guided post-training as an effective strategy for improving both distributional accuracy and biological fidelity in perturbation prediction.