arXiv:2606.30695q-bio.QMcs.AI2026-06

新模型预测药物对单细胞的基因表达和增殖状态影响,更准。

Modeling Cell-Cycle-Aware Single-Cell Drug Perturbation Responses

论文配图:Modeling Cell-Cycle-Aware Single-Cell Drug Perturbation Responses
图 1 · 摘自论文原文
  • 基于细胞周期信号构建无输入依赖的预测框架
  • 相位预测准确率达96.09%,全基因集拟合优度0.9093
  • 适合研究药物对细胞分裂的影响,尤其关注药效机制

单细胞药物扰动模型需同时捕捉转录响应强度与治疗是否改变细胞增殖状态。由于细胞周期常被视为干扰因素,现有基准处理极少将药物诱导的周期变化作为主要预测目标。本文提出scCycleMol,基于标准化的24小时SciPlex3基准(含635,541个细胞、186种扰动、188种化合物嵌入、3种细胞系、4种剂量加DMSO、5,080个基因),构建了细胞周期感知的扰动预测框架。该模型从处理后状态推导细胞周期监督信号,并应用于预测表达结果,不将周期阶段作为输入协变量。模型包含可学习的全表达周期头,采用循环式G1/S/G2M目标。评估了仅读出监督(停梯度)与闭环监督(反向传播通过解码器、剂量-响应模块及药物表示)效果。对比不同分子表征与预训练来源,以分离细胞周期目标的影响。在匹配预处理条件下,闭环细胞周期监督使相位预测准确率提升0.54–0.62点,同时保持全基因集平均R²与无周期信息的chemCPA模型相差不超过0.003;Tahoe预训练的读出监督循环变体实现最高相位准确率0.9609。

原文摘要 · Abstract (English)

Single-cell drug perturbation models should capture transcriptional response magnitude and whether a treatment changes the proliferative state of the cell. This is difficult because cell-cycle variation is often treated as a nuisance factor, and benchmark processing rarely makes drug-induced phase changes a primary prediction target. We introduce scCycleMol, a cell-cycle-aware perturbation prediction framework built on a curated 24-hour SciPlex3 benchmark with standardized molecule identities, dose and cell-line metadata, modeled genes, and expression-derived cell-cycle supervision. scCycleMol derives cell-cycle supervision from the treated state and applies it to predicted treated expression without using phase as an input covariate. The model includes a learnable full-expression cell-cycle head with circular G1/S/G2M targets, and we evaluate readout-only supervision (with stop-gradient) versus closed-loop supervision (backpropagating through decoder, dose-response module, and drug representation). We also compare molecular representations and pretraining sources to isolate the effect of the cell-cycle objective. On a processed 24-hour SciPlex3 benchmark (635,541 cells, 186 perturbations, 188 compound embeddings, 3 cell lines, 4 doses plus DMSO, 5,080 genes), the best LINCS-pretrained circular variant reaches 0.9093 mean all-gene R-squared and 0.6843 mean DE-gene R-squared. Under matched preprocessing, closed-loop cell-cycle supervision improves phase accuracy by 0.54-0.62 points while keeping mean all-gene R-squared within 0.003 of matched chemCPA no-cell-cycle models; Tahoe-pretrained readout-only circular supervision achieves the strongest phase accuracy at 0.9609.

单细胞药物扰动细胞周期生成模型

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