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cs.LGq-bio.QM Dongxia Wu, Shiye Su, Yuhui Zhang et al. · Mar 23, 2026

Virtual cell modeling aims to simulate cellular responses to drug perturbations in silico, but existing flow-matching models optimize only pixel-level reconstruction and can produce biologically implausible outputs like nuclei outside cytoplasm. CellFluxRL addresses this by post-training the state-of-the-art CellFlux model with reinforcement learning, using seven manually designed reward functions spanning biological function (mode of action), structural validity (nuclear containment), and morphological statistics (size/count). The approach reveals a systematic framework for enforcing physical constraints through differentiable optimization, achieving consistent improvements across all biological metrics while maintaining image quality.

Building virtual cells with generative models to simulate cellular behavior in silico is emerging as a promising paradigm for accelerating drug discovery. However, prior image-based generative approaches can produce implausible cell images that violate basic physical and biological constraints. To address this, we propose to post-train virtual cell models with reinforcement learning (RL), leveraging biologically meaningful evaluators as reward functions. We design seven rewards spanning three categories-biological function, structural validity, and morphological correctness-and optimize the state-of-the-art CellFlux model to yield CellFluxRL. CellFluxRL consistently improves over CellFlux across all rewards, with further performance boosts from test-time scaling. Overall, our results present a virtual cell modeling framework that enforces physically-based constraints through RL, advancing beyond "visually realistic" generations towards "biologically meaningful" ones.