Single-Cell RNA Sequencing

Also known as scRNA-seq

Follow this topic Ask about this topic

Momentum

3 papers in the last four weeks, against 1 the four weeks before. 0.0% of all new papers.

Jul 13Week of Sep 28

Latest papers 29

Oct 8, 2026cs.AI

Finsler Flow Matching: Dynamics-Aware Geodesic Interpolation for Single-Snapshot Trajectory Inference

Single-cell snapshot data can resolve a continuum of cellular states but do not uniquely determine the dynamics governing transitions between them. However, additional dynamical information can often be encoded in a cell-cell Markov transition kernel. Existing generative approaches for single cell trajectory inference either infer transport only from population marginals, impose a symmetric geometry on the state space, or incorporate directionality through a single velocity vector at each observed state. We introduce Finsler Flow Matching (FFM), a framework for learning continuous stochastic dynamics from discrete Markov transition graphs. We use the first and second local moments to construct a Finsler structure motivated by the Freidlin--Wentzell action, where the second moment determines anisotropic accessibility and the first moment introduces a preferred direction of motion. We learn neural approximations of the resulting directed geodesics, use their Finsler cost to construct source-target couplings, and define geometry-aware stochastic conditional paths that can be distilled into a continuous generative process through simulation-free score and flow matching. Across synthetic and single-cell trajectory inference benchmarks, FFM improves recovery of withheld intermediate populations, particularly when the transition dynamics are strongly directional or anisotropic. Our results provide a principled route from discrete transition probabilities to continuous generative dynamics while retaining both directional and diffusive structure.

Niklas Canova, Jonas Simon Fleck

Institute of Human Biology (IHB), Roche, Basel, Switzerland

Flow-Based Generative Modeling Single-Cell Transcriptomics Single-Cell RNA Sequencing Conditional Flow Matching

Sep 30, 2026q-bio.GN

CellMSA: Context Modeling for Single-Cell Representation Learning

Single-cell transcriptomics enables profiling of cellular states at unprecedented resolution, but its high dimensionality, sparsity, and technical batch effects pose significant challenges for representation learning. Existing single-cell foundation models typically encode each cell independently or only model cells from the same batch for denoising, thereby underutilizing the rich relational information across batches and cell types to model gene expression patterns. We argue that single-cell models can benefit from more informative cell-context modeling. By comparing consistency and variation across cells, models can capture fine-grained gene-gene dependencies associated with cell states, which are essential for learning high-quality representations. Inspired by the use of multiple sequence alignment (MSA) context in protein modeling, we propose CellMSA, a single-cell representation learning framework that introduces an MSA-inspired inductive bias into transcriptomic modeling. For each target cell, CellMSA retrieves relevant cells from different batches and biologically related cell types as context, and summarizes cross-cell patterns into a context-dependent gene-pair representation. This representation is then injected into a pair-aware target-cell encoder for fine-grained representation learning. We pretrain CellMSA on a large-scale human single-cell corpus of approximately 109 million cell observations, including 65.6 million primary observations. Experiments show that our framework consistently outperforms existing methods across multiple benchmarks. Code is available at the following repository: https://github.com/PharMolix/CellMSA.

Suyuan Zhao, Minghao Liu, Yizhen Luo +1

Institute for AI Industry Research (AIR), Tsinghua University · Department of Computer Science and Technology, Tsinghua University · Tsinghua Institute of Multidisciplinary Biomedical Research (TIMBR), Tsinghua University +2

Representation Learning Single-Cell Transcriptomics Single-Cell RNA Sequencing

Sep 30, 2026cs.LG

scTrilemma: Balancing Identity, Invariance, and Fidelity in Single-Cell Representation Learning

Single-cell RNA-seq representation learning is fundamentally label-free: cell identities, states, and contexts are not fixed training targets, so what constitutes signal or nuisance is analysis-dependent. A single representation must therefore preserve biological identity and state, remain robust to nuisance context, and retain the gene-level variation needed for expression analysis, three demands we call the representation trilemma. To tackle this problem, we introduce scTrilemma, a latent-bottleneck VAE that routes expression-derived variation to the embedding, the decoder, or the prior rather than forcing all of it through one embedding. It gates gene tokens by expression, routes the cell representation through the decoder, and conditions the prior on unlabeled pseudo-bulk context, under a single reconstruction objective and without target annotations or auxiliary representation losses. In release-based zero-shot evaluation on successive CZ CELLxGENE Census releases, scTrilemma leads all three demands at once and preserves biological-state, differential-expression, and pathway structure across multiple disease settings. Latent interventions further show that context can be removed at almost no cost to the other demands, leaving identity against fidelity as the remaining tension. Code is publicly available at https://github.com/yunhak0/scTrilemma.

Yunhak Oh, Yoonho Lee, Junseok Lee +9

KAIST · Work done during an internship at HITS · HITS

Variational Autoencoders Representation Learning Invariant Representation Learning Single-Cell RNA Sequencing

Sep 14, 2026cs.AI

Towards a knowledge-enhanced single-cell foundation model

Single-cell foundation models (scFMs) increasingly rely on large-scale transcriptomic pretraining, yet expanding pretraining data can yield diminishing gains while substantially increasing computational cost. Our data scaling analyses showed that incorporating biological knowledge, including cell-level text annotation and gene-level regulatory information, provided additional scaling dimension than simply increasing data size. Motivated by this observation, we present scKITE, a simple yet effective scFM that integrates cell-annotation and gene-regulatory supervision into a shared transcriptomic Transformer encoder through lightweight auxiliary decoders. These decoders are used only during pretraining and subsequently discarded, yielding a general-purpose encoder enriched with biological knowledge for downstream applications. With only 179,067 pretraining samples, i.e., less than 0.5% of those used by previous strong scFMs, scKITE outperformed these models across diverse downstream tasks, highlighting knowledge-enhanced pretraining as a promising paradigm for biologically grounded scFMs.

Hanqing Zhang, Jie Bao, Mei Ma +7

College of Animal Science and Technology, China Agricultural University, Beijing 100193, China · College of Information and Electrical Engineering, China Agricultural University, Beijing 100193, China

Language Model Pretraining Single-Cell Transcriptomics Single-Cell RNA Sequencing

Sep 1, 2026q-bio.GN

PopPert: Population-level Joint-Distribution Modeling for Single-Cell Perturbation Prediction

Predicting transcriptional responses to specific perturbations is critical for understanding cellular regulatory mechanisms and accelerating drug discovery. Single-cell RNA sequencing destroys each measured cell, yielding only unpaired populations of control and perturbed cells. However, existing methods typically model perturbation prediction at the single-cell level and assume cell-to-cell correspondence, which conflicts with the unpaired nature of the observed data. To address this challenge, we propose PopPert, a framework that explicitly parameterizes population-level joint gene expression distributions for collective transcriptional state modeling. Given a control population distribution and a perturbation condition, PopPert predicts perturbation-induced changes in distribution parameters, eliminating the need for cell-level correspondence and reducing sensitivity to single-cell noise. To effectively capture gene co-expression patterns, PopPert leverages a low-rank Gaussian Copula to model cross-gene statistical dependencies and construct the joint gene expression distribution, additionally allowing sampling of synthetic perturbed single-cell profiles. Across multiple single-cell benchmarks spanning both genetic and chemical perturbations, PopPert achieves superior overall performance in differential expression recovery, perturbation effect estimation, and population-level distribution matching. These results establish population-level joint distribution learning as an effective paradigm for predicting transcriptional responses from unpaired single-cell populations. Code for PopPert is publicly available at https://github.com/whd1125/PopPert.

Handong Wang, Jiaxin Qi, Haochen Feng +1

Computer Network Information Center, Chinese Academy of Sciences · University of Chinese Academy of Sciences

Single-Cell Perturbation Modeling Single-Cell RNA Sequencing

Jul 31, 2026q-bio.GN

Improving scDiffusion with Sparsity-Biased Classifier-Free Guidance

Single-cell RNA sequencing (scRNA-seq) has become an essential tool in modern cellular biology, and generating accurate synthetic scRNA-seq data is becoming increasingly important. Although diffusion models have achieved promising results in conditional scRNA-seq generation, existing guidance strategies, including classifier guidance and classifier-free guidance (CFG), rely on an unconditional branch trained to approximate the true marginal distribution, which may retain substantial gene-specific structure and limit guidance effectiveness. Inspired by recent work showing that diffusion models can be effectively guided using intentionally degraded references, we propose a sparsity-biased classifier-free guidance (SB-CFG) strategy for scRNA-seq generation. Rather than approximating the assumed "neutral" marginal distribution, SB-CFG introduces a deliberately under-informative sparse reference for the unconditional branch, removing gene identity while preserving only coarse sparsity statistics. This "bad" reference amplifies the contrast between conditional and unconditional predictions, leading to stronger and more effective guidance during sampling. We evaluated SB-CFG as a training-free sampling modification on five publicly available scRNA-seq datasets. Experimental results demonstrate consistent improvements over standard CFG-based sampling in terms of marker gene expression fidelity, cell-type consistency, and sparsity preservation, indicating that SB-CFG better captures biologically meaningful gene expression patterns.

Yu Song, Hao Sun, Ikuko Nishikawa +1

College of Information Science and Engineering, Ritsumeikan University, Osaka, Japan

Classifier-Free Guidance Diffusion Sampling Single-Cell RNA Sequencing

Jul 30, 2026cs.AI

PerturbMap: Cross-Context Transfer of Single-Cell Perturbation Responses

Single-cell perturbation atlases rarely measure every intervention in every cellular context: a query perturbation is often observed in one or more source contexts but missing in the recipient context where its effect is needed. Ignoring those measured responses discards query-specific experimental evidence, whereas copying or weakly calibrating them across contexts risks transferring the wrong signal. We propose PerturbMap, which predicts a missing recipient-context effect by combining a recipient-local low-rank base with accepted proposals that transport the same perturbation's measured source responses through source-to-recipient ridge experts fit on paired training perturbations, with proposal weights determined by route reliability estimated on validation anchors. On the Perturb-CITE-seq melanoma cohort, PerturbMap improves full-effect MSE by 4.1% over a recipient-local low-rank base and achieves lower MSE than FedAvg, zero-response, raw-copy, calibrated-copy, and identity-shuffled affine controls. It remains within

2.82\times10^{-6}

MSE of our centralized token-matched pooled reference, which uses a stronger training interface. A condition-mean specificity diagnostic shows the same direction: same-recipient top-10 counterpart retrieval by cosine increases from 74.5% for the low-rank base to 80.5% for PerturbMap.

Panpan Cui, Yiqi Liu, Wenhao Sun

School of Advanced Interdisciplinary Sciences, University of Chinese Academy of Sciences · Institute of Computing Technology, CAS; University of Chinese Academy of Sciences · 3Hong Kong University of Science and Technology

Single-Cell Perturbation Modeling Cross-Domain Transfer Learning Single-Cell RNA Sequencing

Jul 28, 2026cs.LG

When Does Deep Representation Learning Help Single-Cell Clustering? A Sensitivity-Aware Diagnostic Benchmark for Biomedical AI Pipelines

Single-cell ribonucleic acid sequencing (scRNA-seq) is a foundational technology for precision-medicine workflows that contribute to United Nations Sustainable Development Goal 3 on Good Health and Well-being, and unsupervised clustering is the analytical step that turns raw expression matrices into interpretable cell populations. Practitioners therefore face a recurring engineering decision: is an additional deep representation stage worth its compute and tuning cost, or do classical principal component analysis (PCA) pipelines already suffice? We address this question with a diagnostic benchmark of nine clustering pipelines on ten real datasets (90-5,685 cells, 19,046-41,480 genes, 4-11 cell types), augmented by a partial scVI V2 specialized comparison on seven datasets. The protocol integrates Optuna hyperparameter search, repeated-run robustness, Friedman/Wilcoxon-Holm/TOST testing, and Sobol total-order sensitivity analysis. The contrastive autoencoder achieved the highest mean Adjusted Rand Index (0.7872), but Holm-corrected tests did not establish dominance over the strongest baselines. Per-dataset analysis reveals three reproducible regimes: probabilistic variational autoencoder (VAE) variants help on the smallest datasets, deep autoencoders win on mid-scale data with multi-batch or many-type structure, and classical PCA pipelines remain competitive when linear projection already captures the dominant variation. Sobol indices identify learning rate (

S_T=0.70

) and latent dimensionality (

S_T=0.56

) as the dominant variance contributors, indicating where limited tuning budgets should be allocated. The contribution is therefore a dataset-aware and compute-conscious decision framework for biomedical AI pipelines supporting sustainable healthcare analytics, rather than a universal superiority claim.

Nguyen Thanh Phong, Truong Viet Vu, Nguyen Ha Thu +4

Faculty of Information Technology, Van Lang School of Technology, Van Lang University, Ho Chi Minh City, Vietnam · Faculty of Law, Van Lang University, Ho Chi Minh City, Vietnam

Representation Learning Clustering Unsupervised Clustering Single-Cell RNA Sequencing

Jul 26, 2026cs.LG

SCTA: An Agentic Framework for Stable and Interpretable Target Gene Discovery from Single-Cell RNA Sequencing

Identifying therapeutic target genes from single-cell RNA sequencing (scRNA-seq) data remains a fundamental challenge in translational biology. Unlike bulk assays, scRNA-seq captures heterogeneous cellular states and rare subpopulations, but this same heterogeneity makes target discovery highly sensitive to analytical choices throughout the pipeline, including preprocessing, cell population selection, differential expression analysis, and downstream biological interpretation. As a result, existing workflows and general-purpose analysis agents often produce unstable or difficult-to-interpret target hypotheses, limiting their reliability for disease-focused discovery. We present SCTA (Single-Cell Target Agent), a decision-centric agentic framework for stable and interpretable target gene discovery from scRNA-seq data. Rather than treating analysis as a single general-purpose reasoning task, SCTA decomposes target discovery into specialized agents aligned with key decision points in the single-cell pipeline and constrains downstream reasoning with structured biological evidence. In a representative ablation study on hereditary chronic pancreatitis, we demonstrate that SCTA's full evidence integration yields the most stable target selection across independent runs among the tested configurations, while recovering biologically coherent, disease-relevant mechanisms validated in prior studies. These results suggest that decision-aware agent orchestration tailored to the structure of single-cell analysis can improve the robustness, interpretability, and practical utility of target discovery in precision medicine.

Shuyu Chen, Chen Zhu, Ye Zhang +3

Siebel School of Computing and Data Science University of Illinois Urbana-Champaign Champaign, IL, USA · School of Information Sciences University of Illinois Urbana-Champaign Champaign, IL, USA · Novartis Biomedical Research Biomedical Research Cambridge, MA, USA +1

AI Agents for Scientific Discovery Scientific Workflow Automation Single-Cell RNA Sequencing Drug Discovery

Jul 6, 2026cs.LG

Score Distributions, Not Cells: Evaluating Single-Cell Perturbations Under Class Overlap

Most classification problems assume the classes are roughly separable, so that an individual sample can usually be assigned to one class. Single-cell perturbation data violates this assumption: two perturbations can produce different populations of cells while overlapping so much that an individual cell could belong to either. Per-cell accuracy then measures this overlap rather than model quality. We see this on Tahoe-100M and the Virtual Cell Challenge, where a linear classifier, an MLP, and a Transformer all plateau near macro-F1 0.2-0.3 even though almost every pair of perturbations is statistically distinguishable. The fix is to score perturbations across the whole population rather than cell by cell. We average a classifier's per-cell probability vectors over all cells of a perturbation to form a population profile, then rank candidate perturbations by this profile; we call the resulting score the Classifier Discrimination Score (CDS). Taking the top-ranked class recovers the winning perturbation. It needs no retraining, costs linear time in the number of cells, and recovers near-perfect identification from the same weak models. CDS differs from the pseudobulk-based Perturbation Discrimination Score (PDS) used in recent benchmarks only in where the average is taken, raw gene expression for PDS versus a learned discriminative space for CDS, and identifies the true perturbation more reliably on both datasets, with the gap widening as cells grow scarce. Because a metric that misranks the ground truth will misrank the models scored against it, per-cell accuracy and raw-pseudobulk scores should be used with caution when comparing perturbation models.

Youssef Marrakchi, Davide D'Ascenzo, Sebastiano Cultrera di Montesano

Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA, USA. · Department of Computer Science, University of Milan, Milan, Italy. · Department of Control and Computer Engineering, Politecnico di Torino, Torino, Italy. +1

Single-Cell Perturbation Modeling Classification Single-Cell RNA Sequencing

Jun 29, 2026q-bio.QM

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

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.

Dingping Zhao, Jie Lin, Feng Xu +1

Division of Pharmacognosy, School of Pharmaceutical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China · Department of Computer Science at School of Informatics, Xiamen University, Xiamen, China · Peking University Health Science Center, Peking University, Beijing, China

Single-Cell Perturbation Modeling Single-Cell RNA Sequencing Molecular Representation Learning

Jun 26, 2026cs.LG

scKDGM: KAN-guided Dynamic Graph Masked Learning for Single-Cell RNA-seq Clustering

Single-cell RNA sequencing (scRNA-seq) clustering is essential for identifying cell types, but high dimensionality, sparsity, dropout, and technical noise hinder robust expression representation and cell graph construction. Existing masked autoencoders mainly use expression recovery for feature reconstruction, while graph clustering methods usually depend on fixed KNN graphs and do not feed recovered expression back into graph optimization. We propose scKDGM, a KAN-guided dynamic graph masked learning framework for scRNA-seq clustering. scKDGM uses graph-aware distribution preserving gene masking (GDP-Mask) to perturb cell identity, a KAN-based TAKGCN encoder to learn masked-view representations, mask-guided expression recovery to construct a dynamic graph, and cross-view contrastive learning to transfer recovery signals into topology updates. A ZINB loss models overdispersion and zero inflation. Experiments on 12 real scRNA-seq datasets show that scKDGM outperforms 10 baselines in average NMI and ARI.

Jun Tang, Pengwei Hu, Sicong Gao +3

College of Computer and Information Science, Southwest University, Chongqing, China · Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, China

Graph SSL Clustering Dynamic Graph Learning Graph Clustering Single-Cell RNA Sequencing

Jun 17, 2026cs.LG

scGTN: Deep Siamese Graph Transformer Network for Single-cell RNA Sequencing Clustering

Single-cell RNA sequencing (scRNA-seq) serves a pivotal role in characterizing gene expression at the cellular level, enabling the identification of cell types and advancing the understanding of cellular heterogeneity. Despite the significant progress in scRNA-seq data clustering, we argue that current methods always ignore the sparsity and noise, as well as the complex intercellular structural information inherent in scRNA-seq data. Toward this end, in this paper, we propose a novel single-cell RNA-seq clustering framework via deep Siamese Graph Transformer Network (termed scGTN), which explicitly integrates gene expression profile and intercellular structural dependencies for cell clustering. In particular, we formulate scRNA-seq data as a graph and construct two augmented graph views that serve as dual views to capture complementary intercellular information. Then, a Siamese graph transformer network is employed to explicitly incorporate shortest-path information and node-wise distances for capturing richer structural relationships between cells. Finally, we employ an optimal transport strategy to guide the cell clustering in a self-supervised manner. Extensive experiments on multiple benchmark scRNA-seq datasets demonstrate that our scGTN consistently outperforms existing methods. Our code is available at https://github.com/W-RMSL/scGTN.

Jinke Wu, Yifan Wang, Siyu Yi +5

Sichuan University · University of International Business and Economics · Great Bay University +1

Graph SSL Clustering Graph Clustering Graph Transformer Single-Cell RNA Sequencing

Jun 11, 2026cs.LG

scLLM-DSC: LLM-Knowledge Enhanced Cross-Modal Deep Structural Clustering for Single-Cell RNA Sequencing

Clustering is fundamental to scRNA-seq analysis, serving as a cornerstone for identifying cell populations and resolving tissue heterogeneity. However, existing methods focus on mining numerical statistical patterns, suffering from semantic agnosticism by neglecting the intrinsic biological functions encoded by genes. While Large Language Models (LLMs) offer promising semantic capabilities, their direct adaptation to cell clustering is hindered by the structural mismatch between generative pre-training objectives and discriminative downstream tasks. To bridge this gap, we propose scLLM-DSC, a novel LLM-Knowledge Enhanced Cross-Modal Deep Structural Clustering framework. Diverging from data-driven paradigms, scLLM-DSC establishes a semantically-grounded representation by synergizing two views: a Knowledge-Driven Semantic View derived from NCBI gene priors and contextualized Cell2Sentence embeddings, and a Structure-Aware Topological View extracted via a graph-guided encoder. Crucially, we introduce a cross-modal contrastive alignment mechanism to enforce consistency between biological semantics and transcriptomic features within a unified latent space. Extensive benchmarks demonstrate that scLLM-DSC significantly outperforms eleven state-of-the-art baselines in clustering accuracy.

Ping Xu, Pengjiang Li, Tian Du +6

Computer Network Information Center, Chinese Academy of Sciences, Beijing, China · University of Chinese Academy of Sciences, Beijing, China · School of Computing and Information Technology, Great Bay University, Dongguan, China +2

Clustering Unsupervised Clustering Multimodal Embedding Single-Cell RNA Sequencing

Jun 8, 2026q-bio.GN

Integrating gene regulatory priors into Transformer attention with scTransformer for interpretable scRNA-seq analysis

Motivation: Transformer-based models are increasingly applied to large-scale single-cell transcriptomics, showing strong performance through self-supervised learning on millions of cells. However, most existing approaches treat genes as independent features, and largely ignore prior biological knowledge, which limits interpretability and robustness. In this paper, we explore whether explicitly incorporating gene regulatory information can improve both model performance and biological insight. Results: We present scTransformer, the first Transformer-based approach that builds a priori knowledge of biological mechanisms into the model's attention patterns. By constraining information flow according to known regulatory structures, the model learns representations that are more biologically meaningful. We evaluate scTransformer on a disease-relevant single-nucleus RNA-seq dataset using supervised cell-type classification. Compared to standard Transformers, our approach improves classification accuracy, enhances separation of cell types in embedding space, and produces attention patterns consistent with known regulatory programs. Overall, our results demonstrate that embedding biological structure into Transformer models can enhance interpretability without sacrificing performance, offering a principled step toward biologically grounded foundation models for single-cell omics.

Mikele Milia, Louis Fabrice Tshimanga, Henning Mueller +2

Department of Information Engineering, University of Padova, Padova, Italy · Department of Neuroscience, University of Padova, Padova, Italy · Padova Neuroscience Center, Padova, Italy +3

Transformer Interpretability Transformer Attention Scientific ML Genomics Single-Cell RNA Sequencing

Jun 5, 2026cs.LG

scCBGM: Interpretable Single-Cell Counterfactual Editing

Understanding cellular phenotypes and how they respond to perturbations is critical for disease biology and therapeutic design. Single-cell RNA sequencing enables characterization at cellular resolution, yet the combinatorial space of conditions makes exhaustive experimental mapping infeasible. We introduce single-cell Concept Bottleneck Generative Models (scCBGM), a framework for interpretable and precise counterfactual editing of individual cells. scCBGM adapts concept bottleneck architectures for single-cell data through decoder skip connections and a cross-covariance penalty that promotes disentanglement without dimensional constraints. We extend the framework to flow matching models, enabling concept-guided editing in both encoding-decoding and generation regimes. To enable rigorous evaluation, we develop a synthetic benchmark with ground-truth counterfactuals. Across multiple real datasets, scCBGM demonstrates superior performance in combinatorial generalization and counterfactual prediction, supported by cell-level validation on synthetic data and population-level benchmarks on real datasets.

Alma Andersson, Aya Abdelsalam Ismail, Edward De Brouwer +6

Genentech · Guide Labs · Department of Computer Science, New York University +1

Concept Bottleneck Models Causal Counterfactual Generation Single-Cell Perturbation Modeling Single-Cell RNA Sequencing

Jun 4, 2026q-bio.GN

Single-Cell Cross-Modal Transfer by Adversarial Fine-Tuning of Foundation Models

Spatial transcriptomics (ST) is a powerful tool for exploring biological properties dependent on structure, proximity, and interaction in tissue. The methods underpinning ST are developing rapidly but are limited in their ability to profile many thousands of genes at a subcellular scale. Although dissociated from tissue, it is known that the whole-transcriptome readouts of cells in single-cell RNA sequencing (scRNA-seq) retain information about their former in situ neighbourhoods, motivating computational methods to recover it. While paired ST and scRNA-seq datasets are scarce, each modality in its own right is abundantly available. We therefore propose to perform cross-modal translation between unpaired ST and scRNA-seq data. In this work we show that a single-cell foundation model can perform this translation via adversarial fine-tuning. We demonstrate that our method performs favourably against methods built for multi-omics translation.

Joseph Boyd, Matthew Lyon, Martino Mansoldo +2

GSK.ai, GlaxoSmithKline, London, United Kingdom.

Spatial Transcriptomics Fine-Tuning Single-Cell RNA Sequencing

Jun 2, 2026q-bio.MN

BRIDGE: Biological Evidence Refinement and Heterogeneous Dynamic Gating for Gene Regulatory Networks

Motivation: Gene regulatory network inference from single-cell RNA sequencing (scRNA-seq) data is important for uncovering cell-state-specific transcriptional programs. However, scRNA-seq measurements are sparse and noisy, and experimentally validated TF-target interactions remain limited, making reliable inference challenging. Although graph neural networks have advanced GRN prediction, existing methods often rely on biologically unconstrained graph augmentation, such as random edge perturbation, and insufficiently control information transfer between genes and cells. These limitations may distort regulatory structures and weaken robustness under noisy and weakly supervised settings. Results: To address these issues, we propose an innovative framework named Biological Evidence Refinement and Heterogeneous Dynamic Gating for Gene Regulatory Networks (BRIDGE). BRIDGE extracts gene and cell representations from the expression matrix and its matrix dual, and performs contrastive learning in the gene space and cell space between self and neighbors across the co-expression-refined regulatory view and the original graph. It then applies heterogeneous gated encoding to adaptively regulate information transfer between genes and cells, enabling robust transcription factor-to-target gene prediction. Experiments on benchmark datasets spanning three network types and seven cell types show that BRIDGE achieves state-of-the-art AUROC and AUPRC in most settings. In particular, on Specific networks, BRIDGE improves average AUPRC by 5% over the second-best baseline, GCLink. In cross-cell-type few-shot transfer, BRIDGE consistently outperforms GCLink and GENELink across all six target cell types. A case study on hESC further supports the biological relevance of the predictions, with 9 of the top 10 and 46 of the top 100 novel TF-target interactions validated by ChIPBase.

Ziyang Dong, Shanwen Tan, Hengchuang Yin +5

College of Computer Science, Sichuan University, Chengdu, 610065, China · Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, 830011, China · School of Mathematics, Sichuan University, Chengdu, 610065, China +2

Heterogeneous GNNs Graph SSL Gene Regulatory Network Inference Single-Cell RNA Sequencing

May 28, 2026cs.LG

CellBRIDGE: Learning Cellular Trajectories via Interaction-Aware Alignment

Inferring dynamics from population snapshots is a fundamental challenge in machine learning and biology. In scRNA-sequencing (scRNA-seq), destructive measurements preclude direct tracking of individual cells across time, making trajectory inference underdetermined. Optimal Transport (OT) provides a principled framework for snapshot alignment, but a long-standing modeling question is which cost functions yield biologically meaningful couplings. Standard OT approaches rely on gene-expression distances, implicitly treating cells as independent points and neglecting structured cell-cell communication mediated by ligand-receptor signaling. We introduce CellBRIDGE (Cell-Based Regularized Interaction-Driven Gene Expression), which augments feature-based OT with a directed, typed interaction cost derived from ligand-receptor activity. By explicitly modeling cell-cell communication, CellBRIDGE improves cross-snapshot couplings and downstream trajectory estimates across synthetic and real scRNA-seq datasets relative to feature-only baselines. Notably, CellBRIDGE enables mechanistically interpretable in silico perturbations: on lung cancer data, silencing specific ligand-receptor pairs induces trajectory shifts that recapitulate expected effects of targeted pathway inhibition.

Silas Ruhrberg Estévez, Nicolas Huynh, Tennison Liu +4

DAMTP, University of Cambridge · Francis Crick Institute · University of Colorado Anschutz Medical Campus

Single-Cell Transcriptomics Optimal Transport Single-Cell RNA Sequencing

May 27, 2026cs.LG

Geometry-First Generative Spatial Single-Cell Reconstruction

Single-cell RNA sequencing (scRNA-seq) profiles large numbers of cells but loses spatial context, whereas spatial transcriptomics (ST) preserves partial spatial structure at lower resolution. Most existing integration methods either deconvolve spot mixtures or map cells onto a measured spot lattice, which ties reconstructions to a fixed grid and slide-specific coordinate systems, a limitation that is especially problematic in unpaired settings. We propose GEARS, a geometry-first framework that reconstructs an intrinsic single-cell spatial geometry guided by ST, without relying on cell-type labels, histological images, or cell-to-spot assignment. GEARS first learns a domain-invariant expression encoder that aligns ST spots and dissociated cells, and then trains a permutation-equivariant generator with a diffusion-based refiner with EDM-style preconditioning to generate local spatial geometries under pose-invariant supervision derived from ST coordinates. At inference, GEARS reconstructs geometry on many overlapping subsets of scRNA-seq cells, aggregates predicted pairwise distances across subsets, and solves a global distance-geometry problem to obtain canonical two-dimensional coordinates and a dense distance matrix. Extensive quantitative and qualitative experiments, including cross-section generalization, show that GEARS consistently improves global distance preservation, local neighborhood fidelity, and spatial distribution alignment compared to strong spatial mapping and deconvolution baselines.

Ehtesamul Azim, Muhtasim Noor Alif, Tae Hyun Hwang +2

University of Central Florida Orlando, Florida, USA · Vanderbilt University Medical Center Nashville, Tennessee, USA · Arizona State University Tempe, Arizona, USA

Spatial Transcriptomics Genomics Single-Cell RNA Sequencing

May 25, 2026cs.LG

Learning Latent Dynamical Causal Processes for Single-Cell Perturbation Prediction

Single-cell perturbation prediction aims to infer how cells respond to unseen interventions and to achieve out-of-distribution (OOD) generalization, providing a computational route to understanding how perturbations reshape cellular programs over time. Existing machine learning methods have made important progress, but typically capture only one side of the response. Latent causal approaches seek mechanisms that support generalization and interpretation, yet often treat perturbation effects as static outcomes. Temporal models describe how gene expression changes across time, but usually do not explicitly recover the latent causal generative mechanisms driving these changes. In practice, perturbation effects are both latent and dynamical: interventions act through unobserved cellular programs, whose states evolve over time and give rise to observed expression profiles. Motivated by this view, we propose a latent dynamical causal generative model for single-cell perturbation data that jointly captures latent cellular programs, perturbation-conditioned mechanisms, and temporal evolution. We further provide an identifiability analysis showing that, under suitable conditions, the latent causal variables are recoverable up to standard equivalence classes. Guided by this analysis, we develop CITE-VAE, a learning framework for recovering latent cellular programs and their perturbation-driven dynamics from single-cell sequencing data. Experiments on Causal-3DIdent validate the theoretical results and the effectiveness of the proposed method in controlled settings. Additional experiments on real-world CRISPR-based single-cell perturbation data show improved generalization to unseen perturbations compared with state-of-the-art baselines, highlighting the practical robustness of our approach.

Wenkang Jiang, Yuhang Liu, Erdun Gao +3

Causal Representation Learning Latent Dynamics Modeling Single-Cell Perturbation Modeling Causal Identifiability Single-Cell RNA Sequencing

May 18, 2026cs.LG

scHelix: Asymmetric Dual-Stream Integration via Explicit Gene-Level Disentanglement

A critical challenge in single-cell RNA sequencing (scRNA-seq) integration is resolving the tension between eliminating batch effects and maintaining biological fidelity. While recent evidence indicates that batch effects manifest heterogeneously across genes, most existing methods process the transcriptome uniformly, frequently resulting in over-correction and loss of subtle biological signals. To address this, we present scHelix, a dataset-adaptive framework that fundamentally changes how features are processed by explicitly partitioning genes into domain-invariant Anchors and domain-sensitive Variants at the input level. scHelix utilizes a dual-stream sparse diffusion encoder equipped with stop-gradient graph caching to efficiently learn multi-scale structural representations. The core of our approach is a novel asymmetric Align-Refine-Fuse protocol: the unstable Variant stream is first aligned to the robust topology of the Anchor stream, followed by a conservative refinement phase where the Anchor stream absorbs denoised details via bounded residual gating. This divide-and-conquer architecture prevents shortcut learning and ensures robust batch removal without compromising the integrity of biological clusters. Extensive benchmarking demonstrates that scHelix outperforms state-of-the-art methods.

Xichen Yan, Zelin Zang, Changxi Chi +8

Jinan University · Westlake University · HKISI +1

Representation Disentanglement Multi-Scale Feature Fusion Single-Cell RNA Sequencing

May 12, 2026cs.LG

scShapeBench: Discovering geometry from high dimensional scRNAseq data

High-dimensional point cloud data arise across many scientific domains, especially single-cell biology. The shapes or topologies of these datasets determine the types of information that can be extracted. For example, clustered data supports cell-type identification, trajectory structures support transition analysis, and archetypal structures capture continua of cellular behaviors. Existing analysis pipelines often assume a specific shape. The standard Seurat pipeline combines UMAP visualization with Louvain clustering and therefore assumes clustered data, while tools such as Monocle and SPADE assume tree-like structures, and flow-based models such as MIOFlow and Conditional Flow Matching target trajectories. Choosing which pipeline to apply is therefore often left to bioinformaticians who visually inspect datasets before selecting an analysis strategy. With the rise of agentic AI scientists, automating shape detection is increasingly important for selecting downstream analysis pipelines. To address this problem, we introduce scShapeBench, a benchmark dataset for shape detection containing both synthetic and expert-annotated single-cell datasets. Synthetic datasets are sampled from ground-truth skeleton graphs with controlled variance. Real single-cell datasets are curated from diverse sources and annotated by experts into four categories: clusters, single trajectory, multi-branching, and archetypal. We additionally introduce scReebTower, a baseline method that uses diffusion geometry to extract Reeb graphs and connect visualization with pipeline selection. We provide topology-aware evaluation metrics and compare scReebTower against PAGA and Mapper on synthetic and real data. Our results indicate that scReebTower outperforms existing baselines. Overall, our contributions span benchmarks, evaluation metrics, and a baseline for automated shape detection in single-cell data.

Andrew J Steindl, João Felipe Rocha, Brian Tshilengi Di Bassinga +13

Yale University · Mila / Université de Montréal · Garvan Institute of Medical Research +2

Single-Cell RNA Sequencing Topological Data Analysis

May 8, 2026cs.LG

Prototype Guided Post-pretraining for Single-Cell Representation Learning

Single-cell representation learning (SCRL) from gene expression data offers a way to uncover the complex regulatory logic underlying cellular function. Inspired by large language models in natural language modeling, several single-cell pretrained models have recently been proposed that treat genes as tokens and cells as sentences. However, these models are fundamentally limited by the long-tailed nature of cell-type distributions and struggle to generalize under covariate shifts in gene expression data. While fine-tuning is often used to mitigate these issues, we observe that performance remains bounded. To address this challenge, we introduce CellRefine, a post-pretraining method that operates between the pretraining and fine-tuning stages of a single-cell foundation model. CellRefine uses a multi-faceted objective that incorporates marker-gene sets as structural priors to guide post-pretraining and refine the latent embedding manifold of cells. Across multiple computational biology tasks, empirical results show that CellRefine consistently improves downstream performance, yielding gains up to 15%.

Sachini Weerasekara, Natasha Darras, Sagar Kamarthi +2

Sachini Weerasekara∗ · Natasha Darras · Sagar Kamarthi +2

Representation Learning Continued Pretraining Single-Cell Transcriptomics Single-Cell RNA Sequencing

May 7, 2026cs.CL

GATHER: Convergence-Centric Hyper-Entity Retrieval for Zero-Shot Cell-Type Annotation

Zero-shot single-cell cell-type annotation aims to determine a cell's type from a given set of expressed genes without any training. Existing knowledge-graph-based RAG approaches retrieve evidence by expanding from source entities and relying on iterative LLM reasoning. However, in this setting each query contains tens to hundreds of genes, where no single gene is decisive and the label emerges only from their collective co-occurrence. Such hyper-entity queries fundamentally challenge local, entity-wise exploration strategies, which reason from individual genes, leading to poor scalability and substantial LLM cost. We propose GATHER (Graph-Aware Traversal with Hyper-Entity Retrieval), a convergence-centric retriever tailored to hyper-entity queries. It performs global multi-source graph traversal and identifies topological convergence points -- nodes jointly reachable from many input genes. These convergence nodes act as high-information hyper-entities that capture entity synergy. By incorporating node- and path-importance scoring, GATHER selects informative evidence entirely without LLM involvement during retrieval. Instantiated on a self-constructed cell-centric biological knowledge graph (VCKG), GATHER outperforms strong KG-RAG baselines (ToG, ToG-2, RoG, PoG) on two datasets (Immune and Lung), achieving the highest exact-match accuracy (27.45% and 59.64%) with only a single LLM call per sample, compared to 2--61 calls for KG-RAG baselines. Our results demonstrate that convergence nodes compress multi-entity signals into compact, high-information evidence that conveys more per item than multi-hop paths, providing an efficient global alternative to local entity-wise reasoning.

Zhonghui Zhang, Feng Jiang, Shaowei Qin +2

Artificial Intelligence Research Institute, Shenzhen University of Advanced Technology Shenzhen, China · Software College, Northeastern University Shenyang, China

Zero-Shot Learning Graph Retrieval-Augmented Generation Graph-Based Retrieval Information Retrieval Biomedical IR Single-Cell RNA Sequencing+1

May 6, 2026cs.LG

When Does Gene Regulatory Network Inference Break? A Controlled Diagnostic Study of Causal and Correlational Methods on Single-Cell Data

Despite theoretical advantages, causal methods for Gene Regulatory Network (GRN) inference from single-cell RNA-seq data consistently fail to match or outperform correlation-based baselines in many realistic benchmarks, a persistent puzzle which casts doubt on the value of causality for this task. We argue that existing benchmarks are insufficiently controlled to answer this question because they evaluate on real or semi-real data where multiple pathologies co-occur, confounding failure modes, and obscuring the specific conditions under which different inference methods excel or fail. To address this gap, we introduce a controlled diagnostic framework that isolates seven biologically motivated pathologies (dropout, latent confounders, cell-type mixing, feedback loops, network density, sample size, and pseudotime drift) and measure how six representative methods spanning three inference paradigms degrade as each pathology intensifies. Across 6,120 controlled experiments, we find that causal methods genuinely dominate in clean and structurally favorable regimes, but specific pathologies (notably dropout and latent confounders) selectively neutralize their advantages. We further introduce an error-type decomposition that reveals methods with similar aggregate accuracy commit qualitatively different errors. To probe whether single-pathology effects persist when multiple stressors co-occur, we perform an interaction sweep over the three most impactful pathologies and find that their joint effects are sub-additive, while also exposing density-conditional cross-overs invisible to single-dial analysis. Our findings offer a nuanced understanding of when and why different methods succeed or fail for GRN inference, providing actionable insights for method development and practical guidance for practitioners.

Miguel Fernandez-de-Retana, Ruben Sanchez-Corcuera, Unai Zulaika +2

Faculty of Engineering University of Deusto Bilbao, Spain

Causal Discovery Gene Regulatory Network Inference Spurious Correlation Robustness Genomics Single-Cell RNA Sequencing

May 5, 2026q-bio.QM

Donor-Aware scRNA-seq Benchmarks for IBD Classification

Donor-level disease classification from single-cell RNA sequencing (scRNA-seq) requires strict donor-aware cross-validation: naive pipelines that split cells randomly conflate training and test donors, inflating reported performance through pseudoreplication. We present a donor-aware benchmark evaluating three feature representations across two independent IBD cohorts: centered log-ratio (CLR) transformed cell-type composition, GatedStructuralCFN dependency embeddings, and scVI variational autoencoder latent embeddings. The cohorts are the SCP259 ulcerative colitis atlas (UC vs. Healthy, n=30 donors, 51 cell types) and the Kong 2023 Crohn's disease atlas (CD vs. Healthy, n=71 donors, 55-68 cell types across three intestinal regions). Compartment-stratified CLR composition achieves AUROC 0.956 +/- 0.061 on SCP259; GatedStructuralCFN on the same features achieves 0.978 +/- 0.050. In the Kong cohort, CFN achieves its best performance in the colon region (0.960 +/- 0.055 after feature filtering), exceeding linear CLR (0.900 +/- 0.100), while terminal ileum classification is dominated by linear models (CatBoost CLR 0.967 +/- 0.075 vs. CFN 0.811 +/- 0.164). Cross-dataset transfer (CD->UC, four shared cell types) achieves AUC 0.833 with XGBoost CLR; the reverse direction performs at chance. CFN edge stability analysis shows that compartment-wise composition eliminates spurious unit-sum-induced instability present in global composition (Jaccard 0.026 vs. top-20 recurrence 1.0). CFN shows a consistent numerical advantage over linear models in the colon region of CD (AUROC 0.960 vs. 0.900), though no inter-method comparison reached statistical significance at n<=34 donors per region. Compartment-aware feature construction is critical for both classification performance and structural interpretability. Code: https://github.com/Jonathan-321/sfn-scrna-study

Jonathan Muhire

Department of Computer Science, Oklahoma Christian University

Medical Diagnosis Single-Cell RNA Sequencing

Apr 30, 2026q-bio.GN

CellxPert: Inference-Time MCMC Steering of a Multi-Omics Single-Cell Foundation Model for In-Silico Perturbation

In this work, we introduce CellxPert, a scalable multimodal foundation model that unifies single-cell and spatial multi-omics within a common representation space. CellxPert jointly encodes transcriptomic (scRNA-seq), chromatin-accessibility (ATAC-seq), and surface-proteomic (CITE-seq) measurements, while directly incorporating MERFISH and imaging mass-cytometry data as 2D or 3D spatial-visual layers. CellxPert facilitates four key downstream tasks out of the box: (i) cell-type annotation across a broad ontology of 154 largely overlapping identities -- the largest label space addressed to date and a stringent test of fine-grained discrimination, (ii) efficient fine-tuning using Low Rank Adaptation (LoRA), (iii) genome-wide transcriptomic response prediction to in-silico perturbations (ISP), and (iv) seamless multi-omic integration across various assays and platforms. Unlike current single-cell foundation models, which approximate gene perturbations by deleting or reordering tokenized gene expression ranks, CellxPert employs a Metropolis-Hastings sampler whose proposal kernel uses the model's masked conditional distributions to transition to new transcriptomic states conditioned on the perturbed genes. This Markov-chain procedure mitigates out-of-distribution artifacts introduced by abrupt token manipulation and produces trajectories that are biologically interpretable. Evaluations on PBMC68K, Replogle Perturb-seq, Systema, and BMMC benchmarks show that CellxPert surpasses classical and state-of-the-art baselines in cell-type annotation, perturbation response prediction, and multi-omic integration.

Andac Demir, Erik W. Anderson, Jeremy L. Jenkins +1

Novartis Biomedical Research

Single-Cell Perturbation Modeling Genomics Single-Cell RNA Sequencing

Apr 7, 2026q-bio.GN

Transcriptomic Models for Immunotherapy Response Prediction Show Limited Cross-cohort Generalisability

Immune checkpoint inhibitors (ICIs) have transformed cancer therapy; yet substantial proportion of patients exhibit intrinsic or acquired resistance, making accurate pre-treatment response prediction a critical unmet need. Transcriptomics-based biomarkers derived from bulk and single-cell RNA sequencing (scRNA-seq) offer a promising avenue for capturing tumour-immune interactions, yet the cross-cohort generalisability of existing prediction models remains unclear.We systematically benchmark nine state-of-the-art transcriptomic ICI response predictors, five bulk RNA-seq-based models (COMPASS, IRNet, NetBio, IKCScore, and TNBC-ICI) and four scRNA-seq-based models (PRECISE, DeepGeneX, Tres and scCURE), using publicly available independent datasets unseen during model development. Overall, predictive performance was modest: bulk RNA-seq models performed at or near chance level across most cohorts, while scRNA-seq models showed only marginal improvements. Pathway-level analyses revealed sparse and inconsistent biomarker signals across models. Although scRNA-seq-based predictors converged on immune-related programs such as allograft rejection, bulk RNA-seq-based models exhibited little reproducible overlap. PRECISE and NetBio identified the most coherent immune-related themes, whereas IRNet predominantly captured metabolic pathways weakly aligned with ICI biology. Together, these findings demonstrate the limited cross-cohort robustness and biological consistency of current transcriptomic ICI prediction models, underscoring the need for improved domain adaptation, standardised preprocessing, and biologically grounded model design.

Yuheng Liang, Lucy Chhuo, Ahmadreza Argha +8

UNSW BioMedical Machine Learning Lab (BML), School of Biomedical Engineering, UNSW Sydney, Sydney, NSW, 2052, Australia · Garvan Institute of Meidical Research, Sydney, NSW, 2000, Australia · School of Biomedical Engineering, UNSW, Sydney, NSW, 2052, Australia +7

Clinical Outcome Prediction Oncology Single-Cell Transcriptomics Single-Cell RNA Sequencing Cross-Dataset Generalization