NeurIPS 2025 Papers

Unlocking deep and interpretable biological reasoning from complex genomic data remains a major AI challenge limiting scientific progress. While current DNA foundation models excel at representing sequences, they struggle with multi-step reasoning and lack transparent, biologically meaningful explanations. BioReason addresses this by tightly integrating a DNA foundation model with a large language model (LLM), enabling the LLM to directly interpret and reason over genomic information. Through supervised fine-tuning and reinforcement learning, BioReason learns to produce logical, biologically coherent deductions. It achieves major performance gains, boosting KEGG-based disease pathway prediction accuracy from 86% to 98% and improving variant effect prediction by an average of 15% over strong baselines. BioReason can reason over unseen biological entities and explain its decisions step by step, offering a transformative framework for interpretable, mechanistic AI in biology. All data, code, and checkpoints are available at [https://github.com/bowang-lab/BioReason](https://github.com/bowang-lab/BioReason).

We study Diffusion Schrödinger Bridge (DSB) models in the context of dynamical astrophysical systems, specifically tackling observational inverse prediction tasks within Giant Molecular Clouds (GMCs) for star formation. We introduce the Astro-DSB model, a variant of DSB with the pairwise domain assumption tailored for astrophysical dynamics. By investigating its learning process and prediction performance in both physically simulated data and in real observations (the Taurus B213 data), we present two main takeaways. First, from the astrophysical perspective, our proposed paired DSB method improves interpretability, learning efficiency, and prediction performance over conventional astrostatistical and other machine learning methods. Second, from the generative modeling perspective, probabilistic generative modeling reveals improvements over discriminative pixel-to-pixel modeling in Out-Of-Distribution (OOD) testing cases of physical simulations with unseen initial conditions and different dominant physical processes. Our study expands research into diffusion models beyond the traditional visual synthesis application and provides evidence of the models' learning abilities beyond pure data statistics, paving a path for future physics-aware generative models which can align dynamics between machine learning and real (astro)physical systems.

Class-imbalanced learning (CIL) on tabular data is important in many real-world applications where the minority class holds the critical but rare outcomes. In this paper, we present CLIMB, a comprehensive benchmark for class-imbalanced learning on tabular data. CLIMB includes 73 real-world datasets across diverse domains and imbalance levels, along with unified implementations of 29 representative CIL algorithms. Built on a high-quality open-source Python package with unified API designs, detailed documentation, and rigorous code quality controls, CLIMB supports easy implementation and comparison between different CIL algorithms. Through extensive experiments, we provide practical insights on method accuracy and efficiency, highlighting the limitations of naive rebalancing, the effectiveness of ensembles, and the importance of data quality. Our code, documentation, and examples are available at https://github.com/ZhiningLiu1998/imbalanced-ensemble.

Recent guidance methods in diffusion models steer reverse sampling by perturbing the model to construct an implicit weak model and guide generation away from it. Among these approaches, attention perturbation has demonstrated strong empirical performance in unconditional scenarios where classifier-free guidance is not applicable. However, existing attention perturbation methods lack principled approaches for determining where perturbations should be applied, particularly in Diffusion Transformer (DiT) architectures where quality-relevant computations are distributed across layers. In this paper, we investigate the granularity of attention perturbations, ranging from the layer level down to individual attention heads, and discover that specific heads govern distinct visual concepts such as structure, style, and texture quality. Building on this insight, we propose ``HeadHunter", a systematic framework for iteratively selecting attention heads that align with user-centric objectives, enabling fine-grained control over generation quality and visual attributes. In addition, we introduce SoftPAG, which linearly interpolates each selected head’s attention map toward an identity matrix, providing a continuous knob to tune perturbation strength and suppress artifacts. Our approach not only mitigates the oversmoothing issues of existing layer-level perturbation but also enables targeted manipulation of specific visual styles through compositional head selection. We validate our method on modern large-scale DiT-based text-to-image models including Stable Diffusion 3 and FLUX.1, demonstrating superior performance in both general quality enhancement and style-specific guidance. Our work provides the first head-level analysis of attention perturbation in diffusion models, uncovering interpretable specialization within attention layers and enabling practical design of effective perturbation strategies.

Retrosynthesis planning aims to decompose target molecules into available building blocks, forming a synthetic tree where each internal node represents an intermediate compound and each leaf ideally corresponds to a purchasable reactant. However, this tree becomes invalid if any leaf node is not a valid building block, making the planning process vulnerable to the "weakest link" in the synthetic route. Existing methods often optimise for average performance across branches, failing to account for this worst-case sensitivity. In this paper, we reframe retrosynthesis as a worst-path optimisation problem within tree-structured Markov Decision Processes (MDPs). We prove that this formulation admits a unique optimal solution and provides monotonic improvement guarantees. Building on this insight, we introduce Interactive Retrosynthesis Planning (InterRetro), a method that interacts with the tree MDP, learns a value function for worst-path outcomes, and improves its policy through self-imitation, preferentially reinforcing past decisions with high estimated advantage. Empirically, InterRetro achieves state-of-the-art results — solving 100\% of targets on the Retro*-190 benchmark, shortening synthetic routes by 4.9\%, and achieving promising performance using only 10\% of the training data.

The emergence of large language models (LLMs) has opened new opportunities for AI-driven chemical problem solving. However, existing chemical LLMs are typically tailored to specific task formats or narrow domains, limiting their capacity to integrate knowledge and generalize across tasks. Model merging offers a promising route for efficiently combining specialized LLMs into a unified model without access to original training data, which is urgently needed in the chemical domain where in-house data and privacy preservation are critical. However, effective model merging in the chemical domain poses unique challenges: (1) significant disparities among chemical LLMs due to task-specific specialization, and (2) a highly imbalanced distribution of chemical LLMs in targeted downstream tasks, where some are over-benchmarked while others remain underexplored. These challenges intensify model inconsistencies such as parameter interference and accumulated fine-tuning noise, which collectively hinder effective model merging. To this end, we propose Curriculum Model Merging (CMM), a curriculum-based framework that progressively merges expert chemical LLMs in a moderate and continual manner. CMM aims to harmonize their inconsistencies while meantime preserve their domain-specific expertise. Comprehensive experiments on two benchmark datasets show that CMM effectively consolidates task-specific expertise and outperforms the state-of-the-art methods by 29.03\% in terms of overall average performance. Moreover, CMM facilitates chemical knowledge generalization across prediction and generative tasks without sacrificing robustness, exhibiting promising merging performance under both expert-abundant and expert-sparse scenarios.

Tubular-like system shape analysis is quite difficult in geometry and topology, while it is widely used in plants and organs analysis in practice. However, traditional discrete representations such as voxels and point clouds often require substantial storage and may lead to the loss of fine-grained geometric and topological details. To address these challenges, we propose SE(3)-BBSCformerGCN, a novel framework for learning shape-aware representations from continuous tubular topological manifolds with equivariance to rotations and translations. Our approach leverages Ball B-Spline Curve (BBSC) to define tubular manifolds and its functional space. We provide a formal mathematical definition and analysis of the resulting manifolds and the BBSC functional space, and incorporate an equivariant mapping that preserves geometric and topological stability. Compared to the point cloud and voxel based representations, our manifold-based formulation significantly reduces data complexity while preserving geometric attributes together with topological features. We validate our method on the branch classification task for Circle of Willis (CoW) on the TopCoW 2024 dataset and the clinical dataset. Our method consistently outperforms voxel and point cloud based baselines in terms of classification performance, generalization ability, convergence speed, and robustness to overfitting.

In reinforcement learning from human feedback, preference-based reward models play a central role in aligning large language models to human-aligned behavior. However, recent studies show that these models are prone to reward hacking and often fail to generalize well due to over-optimization. They achieve high reward scores by exploiting shortcuts, that is, exploiting spurious features (e.g., response verbosity, agreeable tone, or sycophancy) that correlate with human preference labels in the training data rather than genuinely reflecting the intended objectives. In this paper, instead of probing these issues one at a time, we take a broader view of the reward hacking problem as shortcut behaviors and introduce a principled yet flexible approach to mitigate shortcut behaviors in preference-based reward learning. Inspired by the invariant theory in the kernel perspective, we propose Preference-based Reward Invariance for Shortcut Mitigation (PRISM), which learns group-invariant kernels with feature maps in a closed-form learning objective. Experimental results in several benchmarks show that our method consistently improves the accuracy of the reward model on diverse out-of-distribution tasks and reduces the dependency on shortcuts in downstream policy models, establishing a robust framework for preference-based alignment.

Large-scale machine learning models deliver strong performance across a wide range of tasks but come with significant computational and resource constraints. To mitigate these challenges, local smaller models are often deployed alongside larger models, relying on routing and deferral mechanisms to offload complex tasks. However, existing approaches inadequately balance the capabilities of these models, often resulting in unnecessary deferrals or sub-optimal resource usage. In this work, we introduce a novel loss function called Gatekeeper for calibrating smaller models in cascade setups. Our approach fine-tunes the smaller model to confidently handle tasks it can perform correctly while deferring complex tasks to the larger model. Moreover, it incorporates a mechanism for managing the trade-off between model performance and deferral accuracy and is broadly applicable across various tasks and domains without any architectural changes. We evaluated our method on encoder-only, decoder-only, and encoder-decoder architectures. Experiments across image classification, language modeling, and vision-language tasks show that our approach substantially improves deferral performance.

Time Series Imputation (TSI), which aims to recover missing values in temporal data, remains a fundamental challenge due to the complex and often high-rate missingness in real-world scenarios. Existing models typically optimize the point-wise reconstruction loss, focusing on recovering numerical values (local information). However, we observe that under high missing rates, these models still perform well in the training phase yet produce poor imputations and distorted latent representation distributions (global information) in the inference phase. This reveals a critical optimization dilemma: current objectives lack global guidance, leading models to overfit local noise and fail to capture global information of the data. To address this issue, we propose a new training paradigm, **Glocal** **I**nformation **B**ottleneck (**Glocal-IB**). Glocal-IB is model-agnostic and extends the standard IB framework by introducing a Global Alignment loss, derived from a tractable mutual information approximation. This loss aligns the latent representations of masked inputs with those of their originally observed counterparts. It helps the model retain global structure and local details while suppressing noise caused by missing values, giving rise to better generalization under high missingness. Extensive experiments on nine datasets confirm that Glocal-IB leads to consistently improved performance and aligned latent representations under missingness. Our code implementation is available in [https://github.com/Muyiiiii/NeurIPS-25-Glocal-IB](https://github.com/Muyiiiii/NeurIPS-25-Glocal-IB).

Hybrid language models that combine Attention and State Space Models (SSMs) have been shown to achieve state-of-the-art accuracy and runtime performance. Recent work has also demonstrated that applying pruning and distillation to Attention-only models yields smaller, more accurate models at a fraction of the training cost. In this work, we explore the effectiveness of compressing Hybrid architectures. To this end, we introduce a novel group-aware pruning method for Mamba layers that preserves the structural integrity of SSM blocks and their sequence modeling capabilities. We combine this method with FFN, embedding dimension, and layer pruning, along with knowledge distillation-based retraining to obtain a unified compression recipe for hybrid models. Using this recipe, we compress the Nemotron-H 8B Hybrid model down to 4B parameters with up to $40\times$ fewer training tokens compared to similarly-sized models. The resulting model surpasses the accuracy of similarly-sized models while achieving $\sim2\times$ faster inference throughput, significantly advancing the Pareto frontier.

We study the optimization and sample complexity of gradient-based training of a two-layer neural network with quadratic activation function in the high-dimensional regime, where the data is generated as $y \propto \sum_{j=1}^{r}\lambda_j \sigma\left(\langle \boldsymbol{\theta_j}, \boldsymbol{x}\rangle\right), \boldsymbol{x} \sim \mathcal{N}(0,\boldsymbol{I}_d)$, where $\sigma$ is the 2nd Hermite polynomial, and $\lbrace \boldsymbol{\theta}_j \rbrace _{j=1}^{r} \subset \mathbb{R}^d$ are orthonormal signal directions. We consider the extensive-width regime $r \asymp d^\beta$ for $\beta \in (0, 1)$, and assume a power-law decay on the (non-negative) second-layer coefficients $\lambda_j\asymp j^{-\alpha}$ for $\alpha \geq 0$. We provide a sharp analysis of the SGD dynamics in the feature learning regime, for both the population limit and the finite-sample (online) discretization, and derive scaling laws for the prediction risk that highlight the power-law dependencies on the optimization time, the sample size, and the model width. Our analysis combines a precise characterization of the associated matrix Riccati differential equation with novel matrix monotonicity arguments to establish convergence guarantees for the infinite-dimensional effective dynamics.

Simulating collective decision-making involves more than aggregating individual behaviors; it emerges from dynamic interactions among individuals. While large language models (LLMs) offer strong potential for social simulation, achieving quantitative alignment with real-world data remains a key challenge. To bridge this gap, we propose the \textbf{M}ean-\textbf{F}ield \textbf{LLM} (\textbf{MF-LLM}) framework, the first to incorporate mean field theory into LLM-based social simulation. MF-LLM models bidirectional interactions between individuals and the population through an iterative process, generating population signals to guide individual decisions, which in turn update the signals. This interplay produces coherent trajectories of collective behavior. To improve alignment with real-world data, we introduce \textbf{IB-Tune}, a novel fine-tuning method inspired by the \textbf{I}nformation \textbf{B}ottleneck principle, which retains population signals most predictive of future actions while filtering redundant history. Evaluated on a real-world social dataset, MF-LLM reduces KL divergence to human population distributions by \textbf{47\%} compared to non-mean-field baselines, enabling accurate trend forecasting and effective intervention planning. Generalizing across 7 domains and 4 LLM backbones, MF-LLM provides a scalable, high-fidelity foundation for social simulation.

Speculative decoding has become a widely adopted as an effective technique for lossless inference acceleration when deploying large language models (LLMs). While on-the-fly self-speculative methods offer seamless integration and broad utility, they often fall short of the speed gains achieved by methods relying on specialized training. Cascading a hierarchy of draft models promises further acceleration and flexibility, but the high cost of training multiple models has limited its practical application. In this paper, we propose a novel Cascade Adaptive Self-Speculative Decoding (CAS-Spec) method which constructs speculative draft models by leveraging dynamically switchable inference acceleration (DSIA) strategies, including layer sparsity and activation quantization. Furthermore, traditional vertical and horizontal cascade algorithms are inefficient when applied to self-speculative decoding methods. We introduce a Dynamic Tree Cascade (DyTC) algorithm that adaptively routes the multi-level draft models and assigns the draft lengths, based on the heuristics of acceptance rates and latency prediction. Our CAS-Spec method achieves state-of-the-art acceleration compared to existing on-the-fly speculative decoding methods, with an average speedup from $1.1\times$ to $2.3\times$ over autoregressive decoding across various LLMs and datasets. DyTC improves the average speedup by $47$\% and $48$\% over cascade-based baseline and tree-based baseline algorithms, respectively. CAS-Spec can be easily integrated into most existing LLMs and holds promising potential for further acceleration as self-speculative decoding techniques continue to evolve.

Predicting the binding affinity of protein-ligand complexes plays a vital role in drug discovery. Unfortunately, progress has been hindered by the lack of large-scale and high-quality binding affinity labels. The widely used PDBbind dataset has fewer than 20K labeled complexes. Self-supervised learning, especially graph contrastive learning (GCL), provides a unique opportunity to break the barrier by pretraining graph neural network models based on vast unlabeled complexes and fine-tuning the models on much fewer labeled complexes. However, the problem faces unique challenges, including a lack of a comprehensive unlabeled dataset with well-defined positive/negative complex pairs and the need to design GCL algorithms that incorporate the unique characteristics of such data. To fill the gap, we propose DecoyDB, a large-scale, structure-aware dataset specifically designed for self-supervised GCL on protein–ligand complexes. DecoyDB consists of high-resolution ground truth complexes and diverse decoy structures with computationally generated binding poses that range from realistic to suboptimal. Each decoy is annotated with a Root Mean Square Deviation (RMSD) from the native pose. We further design a customized GCL framework to pretrain graph neural networks based on DecoyDB and fine-tune the models with labels from PDBbind. Extensive experiments confirm that models pretrained with DecoyDB achieve superior accuracy, sample efficiency, and generalizability.

Large language models (LLMs) trained via reinforcement learning with verifiable reward (RLVR) have achieved breakthroughs on tasks with explicit, automatable verification, such as software programming and mathematical problems. Extending RLVR to electronic design automation (EDA), especially automatically generating hardware description languages (HDLs) like Verilog from natural-language (NL) specifications, however, poses three key challenges: the lack of automated and accurate verification environments, the scarcity of high-quality NL-code pairs, and the prohibitive computation cost of RLVR. To this end, we introduce CodeV-R1, an RLVR framework for training Verilog generation LLMs. First, we develop a rule-based testbench generator that performs robust equivalence checking against golden references. Second, we propose a round-trip data synthesis method that pairs open-source Verilog snippets with LLM-generated NL descriptions, verifies code–NL–code consistency via the generated testbench, and filters out inequivalent examples to yield a high-quality dataset. Third, we employ a two-stage "distill-then-RL" training pipeline: distillation for the cold start of reasoning abilities, followed by adaptive DAPO, our novel RLVR algorithm that can reduce training cost by adaptively adjusting sampling rate. The resulting model, CodeV-R1-7B, achieves 68.6 \% and 72.9 \% pass@1 on VerilogEval v2 and RTLLM v1.1, respectively, surpassing prior state-of-the-art by 12$\sim$20 \%, while even exceeding the performance of 671B DeepSeek-R1 on RTLLM. We have released our model, training code, and dataset to facilitate research in EDA and LLM communities.

The high inference demands of transformer-based Large Language Models (LLMs) pose substantial challenges in their deployment. To this end, we introduce *Neural Block Linearization* (NBL), a novel framework for accelerating transformer model inference by replacing self-attention layers with linear approximations derived from Linear Minimum Mean Squared Error estimators. NBL leverages Canonical Correlation Analysis to compute a theoretical upper bound on the approximation error. Then, we use this bound as a criterion for substitution, selecting the LLM layers with the lowest linearization error. NBL can be efficiently applied to pre-trained LLMs without the need for fine-tuning. In experiments, NBL achieves notable computational speed-ups while preserving competitive accuracy on multiple reasoning benchmarks. For instance, applying NBL to 12 self-attention layers in *DeepSeek-R1-Distill-Llama-8B* increases the inference speed by 32% with less than 1% accuracy trade-off, making it a flexible and promising solution to improve the inference efficiency of LLMs.

Graph Neural Networks (GNNs) often encounter significant performance degradation under distribution shifts between training and test data, hindering their applicability in real-world scenarios. Recent studies have proposed various methods to address the out-of-distribution (OOD) generalization challenge, with many methods in the graph domain focusing on directly identifying an invariant subgraph that is predictive of the target label. However, we argue that identifying the edges from the invariant subgraph directly is challenging and error-prone, especially when some spurious edges exhibit strong correlations with the targets. In this paper, we propose $\texttt{PrunE}$, the first pruning-based graph OOD method that eliminates spurious edges to improve OOD generalizability. By pruning spurious edges, $\texttt{PrunE}$ retains the invariant subgraph more comprehensively, which is critical for OOD generalization. Specifically, $\texttt{PrunE}$ employs two regularization terms to prune spurious edges: 1) _graph size constraint_ to exclude uninformative spurious edges, and 2) _$\epsilon$-probability alignment_ to further suppress the occurrence of spurious edges. Through theoretical analysis and extensive experiments, we show that $\texttt{PrunE}$ achieves superior OOD performance and outperforms previous state-of-the-art methods significantly.

Designing de novo 3D molecules with desirable properties remains a fundamental challenge in drug discovery and molecular engineering. While diffusion models have demonstrated remarkable capabilities in generating high-quality 3D molecular structures, they often struggle to effectively control complex multi-objective constraints critical for real-world applications. In this study, we propose an uncertainty-aware Reinforcement Learning (RL) framework to guide the optimization of 3D molecular diffusion models toward multiple property objectives while enhancing the overall quality of the generated molecules. Our method leverages surrogate models with predictive uncertainty estimation to dynamically shape reward functions, facilitating balance across multiple optimization objectives. We comprehensively evaluate our framework across three benchmark datasets and multiple diffusion model architectures, consistently outperforming baselines for molecular quality and property optimization. Additionally, Molecular Dynamics (MD) simulations and ADMET profiling of top generated candidates indicate promising drug-like behavior and binding stability, comparable to known Epidermal Growth Factor Receptor (EGFR) inhibitors. Our results demonstrate the strong potential of RL-guided generative diffusion models for advancing automated molecular design.