Predicting transcriptomic responses to small-molecule perturbations across cell lines is central to drug discovery, but exhaustive profiling of drug-cell combinations is infeasible. We frame molecular perturbation prediction as retrieve-and-aggregate: approximate an unmeasured drug's response in a cell line by aggregating measured responses of a small set of biologically related compounds. We propose LLM-Guided Retrieval (LGR), where a large language model (LLM) ranks candidate neighbor drugs (restricted to those profiled in the target cell line); after which a fixed mean aggregator combines their observed expression deltas to form the prediction. We evaluate on the Tahoe-100M single-cell perturbation atlas under unseen-drug, unseen-cell-line, and open-world regimes. LGR consistently improves over drug mean, ChemCPA, and chemistry-based kNN baselines, with the strongest gains for unseen cell-line generalization, where it achieves higher correlation and lower error than mean baselines. Across settings, LGR improves directional (sign) accuracy of gene regulation, indicating better recovery of biologically meaningful perturbation effects even when magnitude-based metrics are similar. These results suggest that retrieval quality, rather than predictor complexity, is a key driver of zero-shot molecular perturbation prediction, and that LLMs can provide a useful biological prior when used as constrained retrieval modules.
Predicting the effect of an unseen gene knockout perturbation on transcriptomic gene expression remains a highly challenging problem for virtual cell models. Recent progress has been made by leveraging biological knowledge graphs to provide a notion of similar perturbation, allowing for improved extrapolation beyond the set of training perturbations. In this work, we demonstrate that the simplest model to leverage these assumptions - a K-nearest neighbour from the knowledge graph - achieves highly competitive performance on this task, and that this can be improved further using LLMs optimised via reinforcement learning (RL) for predictive performance. Specifically, we find that the K-nearest neighbour approach beats almost all methods on out-of-distribution perturbation prediction, and when a reasoning LLM is trained via RL to make changes to the neighbourhood, it obtains equivalent performance to current state of the art methods on the cell lines from Replogle et al. (2022). We also demonstrate that the RL training improves the LLM's performance on the downstream task of differential expression prediction, despite not being trained on this directly. Overall, these findings demonstrate the efficacy of knowledge graphs as model priors, and show early signs that RL can refine LLMs into generalizable tools for predicting complex biological responses.
Perturbation experiments are central to understanding cellular mechanisms, but remain costly and sparse, motivating prediction of gene expression responses for unobserved conditions. A promising recent direction leverages large language models (LLMs) as "virtual cell" simulators-using stepwise, knowledge-grounded mechanistic reasoning to infer differential expression-pointing toward an interpretable, knowledge-driven paradigm that transcends purely data-driven approaches. However, we find that plausibility is not prediction: despite producing biologically plausible explanations, these methods fail to capture perturbation-specific effects: systematically overestimating differential expression, often underperforming a simple gene-frequency baseline in aggregate evaluations, and collapsing to chance-level performance at the per-gene level. This reveals a reliance on intrinsic gene response tendencies rather than true perturbation reasoning. We trace this failure to how evidence is presented: existing methods evaluate perturbation-gene pairs in isolation, without exposing how related perturbations differ in their effects on the same gene. To address this limitation, we introduce CORE (Contrastive Organization of Relational Evidence), which reframes prediction as a comparison task by organizing evidence into positive and negative outcomes from related perturbations. Using a biomedical knowledge graph for evidence retrieval, CORE improves calibration and substantially boosts perturbation-specific prediction in both LLM-based and non-LLM settings: for example, on drug-perturbation data, CORE-Reasoning improves Qwen3.5-9B aggregate metrics by up to 28.6%, while on generic perturbation data, CORE-Voting raises macro-per-gene AUROC from chance to 0.703 in average across four cell lines. This highlights contrastive evidence organization as essential to reliable LLM-based perturbation reasoning
Large-scale single-cell perturbation atlases make it possible to ask an inverse question: given an observed transcriptional response, which annotated targets and compounds in a fixed library are most consistent with that response? We present \model, a Transformer retrieval model for this closed-library setting. Each input is a cell-level perturbation signature formed by contrasting one treated cell with a cell-line-specific mean DMSO reference. The encoder maps the signature to a target-retrieval vector and a molecular-embedding vector, trained jointly with supervised target losses and structure--transcriptome alignment. We evaluate on Tahoe-100M conditions with mapped target annotations using a within-compound stratified 90/10 condition-pair split of 10,505 training and 1,168 validation drug--cell-line pairs. Because compounds and cell lines can occur in both partitions, the experiment measures held-out condition-pair retrieval rather than generalization to unseen compounds or cellular contexts. In a Monte Carlo evaluation over 38,400 sampled validation cells, \model\ achieved target Recall@10 of 0.408 and Recall@20 of 0.544, together with compound Hit@1 of 0.129, Hit@10 of 0.343, and mean reciprocal rank of 0.205 over a 379-compound bank. A separate diagnostic evaluation produced nearly identical values for the main model and large gains over a random-vector control and post-hoc bag-of-genes controls. These results demonstrate that a single multi-task model can recover both mapped target annotations and recorded compound identities from observed cell-level responses in the evaluated Tahoe-100M closed-library setting. Generalization to unseen compounds and cellular contexts remains to be established.