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JT-SAFE-V2: Safety-by-Design Foundation Model with World-Context Data

arXiv:2605.24414v1 Announce Type: new Abstract: We introduce JT-Safe-V2, a large language model designed to advance the safety and trustworthiness of foundation models, extending our previous JT-Safe model toward a more comprehensive safety-by-design paradigm. JT-Safe-V2 emphasizes the joint optimization of general intelligence and safety-by-design through several key innovations: enriching pre-training data with contextual world knowledge, high-certainty pre-training procedures, and safety strengthening post-training mechanisms for enterprise-oriented agentic capabilities. Building on these safety-enhanced foundation models, we propose Safe-MoMA (Safe Mixture of Models and Agents), a framework that enables traceable and efficient inference through the orchestrated deployment of multiple models and agents. Extensive evaluations demonstrate that JT-Safe-V2 achieves state-of-the-art performance across both general intelligence and safety benchmarks. Moreover, Safe-MoMA reduces inference costs by more than 30\% compared to using the largest standalone model baseline while maintaining comparable performance. To facilitate future research on safety-by-design foundation models, we publicly release the post-trained JT-Safe-V2-35B model checkpoint.

Parameter Efficient Multi-Class Intelligent Scheduling for Multimodal Online Distributed Industrial Anomaly Detection

arXiv:2605.23984v1 Announce Type: cross Abstract: Industrial anomaly detection has attracted significant attention as a fundamental challenge in industrial systems. The rapid advancement of heterogeneous industrial sensors has driven industrial anomaly detection from unimodal to multimodal paradigms. However, existing methods are primarily designed for centralized and offline settings, overlooking the distributed and continuously generated data characteristic of real-world industrial environments. With the advancement of edge intelligence, modern edge devices are increasingly capable of not only data acquisition but also distributed model training, enabling collaborative intelligence across the system. Industrial anomaly detection represents a critical application in this context. Motivated by these challenges, we propose a novel framework termed Multimodal Online Distributed Industrial Anomaly Detection (MODIAD). We first present a comprehensive workflow for MODIAD and then formulate a Multi-class Intelligent Scheduling (MIS) problem to coordinate cross class model updates by balancing data sufficiency and class update frequency. To efficiently solve this problem, we design a Sequential Marginal Gain Greedy (SMG) algorithm that enables effective multi-class training under resource constraints. Furthermore, to improve the computational and communication efficiency during training, we propose an Resource Efficient Class-Wise Low Rank Adaptation (REC-LoRA) strategy, which significantly reduces system overhead while preserving detection performance. Extensive experiments on two representative multimodal industrial anomaly detection datasets, MVTec 3D-AD and Eyecandies demonstrate that the proposed approach achieves superior performance and efficiency under the MODIAD scenario.

NSR-Boost: A Neuro-Symbolic Residual Boosting Framework for Industrial Legacy Models

arXiv:2601.10457v3 Announce Type: replace Abstract: Although the Gradient Boosted Decision Trees (GBDTs) dominate industrial tabular applications, upgrading legacy models in high-concurrency production environments still faces prohibitive retraining costs and systemic risks. To address this problem, we present NSR-Boost, a neuro-symbolic residual boosting framework designed specifically for industrial scenarios. Its core advantage lies in being ``non-intrusive''. It treats the legacy model as a frozen model and performs targeted repairs on "hard regions" where predictions fail. The framework comprises three key stages: First, finding hard regions through residuals, then generating interpretable experts by generating symbolic code structures using Large Language Model (LLM) and fine-tuning parameters using Bayesian optimization, and finally dynamically integrating experts with legacy model output through a lightweight aggregator. Experimental results demonstrate that the framework significantly outperforms state-of-the-art (SOTA) baselines across six public datasets and one private dataset. More importantly, we report the successful deployment of NSR-Boost within the core financial risk control system of Qfin Holdings, where empirical results on real-world online traffic exhibit superior performance improvements and a significant reduction in the bad rate. In conclusion, it effectively captures long-tail risks missed by traditional models and offers a safe, low-cost evolutionary paradigm for industry.

SkillOpt: Executive Strategy for Self-Evolving Agent Skills

arXiv:2605.23904v2 Announce Type: replace Abstract: Agent skills today are hand-crafted, generated one-shot, or evolved through loosely controlled self-revision, none of which behaves like a deep-learning optimizer for the skill, and none of which reliably improves over its starting point under feedback. We argue the skill should instead be trained as the external state of a frozen agent, with the same discipline that makes weight-space optimization reproducible. SkillOpt is, to our knowledge, the first systematic controllable text-space optimizer for agent skills: a separate optimizer model turns scored rollouts into bounded add/delete/replace edits on a single skill document, and an edit is accepted only when it strictly improves a held-out validation score. A textual learning-rate budget, rejected-edit buffer, and epoch-wise slow/meta update make skill training stable while adding zero inference-time model calls at deployment. Across six benchmarks, seven target models, and three execution harnesses (direct chat, Codex, Claude Code), SkillOpt is best or tied on all 52 evaluated (model, benchmark, harness) cells and beats every per-cell competitor among human, one-shot LLM, Trace2Skill, TextGrad, GEPA, and EvoSkill skills. On GPT-5.5 it lifts the average no-skill accuracy by +23.5 points in direct chat, by +24.8 inside the Codex agentic loop, and by +19.1 inside Claude Code. Transfer experiments further show that optimized skill artifacts retain value when moved across model scales, between Codex and Claude Code execution environments, and to a nearby math benchmark without further optimization. Code: https://aka.ms/skillopt

VILAS: A VLA-Integrated Low-cost Architecture with Soft Grasping for Robotic Manipulation

arXiv:2605.02037v2 Announce Type: replace-cross Abstract: We present VILAS, a fully low-cost, modular robotic manipulation platform designed to support end-to-end vision-language-action (VLA) policy learning and deployment on accessible hardware. The system integrates a Fairino FR5 collaborative arm, a Jodell RG52-50 electric gripper, and a dual-camera perception module, unified through a ZMQ-based communication architecture that seamlessly coordinates teleoperation, data collection, and policy deployment within a single framework. To enable safe manipulation of fragile objects without relying on explicit force sensing, we design a kirigami-based soft compliant gripper extension that induces predictable deformation under compressive loading, providing gentle and repeatable contact with delicate targets. We deploy and evaluate three state-of-the-art VLA models on the VILAS platform: pi_0, pi_0.5, and GR00T N1.6. All models are fine-tuned from publicly released pretrained checkpoints using an identical demonstration dataset collected via our teleoperation pipeline. Experiments on a grape grasping task validate the effectiveness of the proposed system, confirming that capable manipulation policies can be successfully trained and deployed on low-cost modular hardware. Our results further provide practical insights into the deployment characteristics of current VLA models in real-world settings.

Break the Brake, Not the Wheel: Untargeted Jailbreak via Entropy Maximization

arXiv:2605.10764v2 Announce Type: replace-cross Abstract: Recent studies show that gradient-based universal image jailbreaks on vision-language models (VLMs) exhibit little or no cross-model transferability, casting doubt on the feasibility of transferable multimodal jailbreaks. We revisit this conclusion under a strictly untargeted threat model without enforcing a fixed prefix or response pattern. Our preliminary experiment reveals that refusal behavior concentrates at high-entropy tokens during autoregressive decoding, and non-refusal tokens already carry substantial probability mass among the top-ranked candidates before attack. Motivated by this finding, we propose Untargeted Jailbreak via Entropy Maximization(UJEM)-KL, a lightweight attack that maximizes entropy at these decision tokens to flip refusal outcomes, while stabilizing the remaining low-entropy positions to preserve output quality. Across three VLMs and two safety benchmarks, UJEM-KL achieves competitive white-box attack success rates and consistently improves transferability, while remaining effective under representative defenses. Our experimental results indicate that the limited transferability primarily stems from overly constrained optimization objectives.

BacktestBench: Benchmarking Large Language Models for Automated Quantitative Strategy Backtesting

arXiv:2605.17937v2 Announce Type: replace-cross Abstract: Quantitative backtesting is essential for evaluating trading strategies but remains hampered by high technical barriers and limited scalability. While Large Language Models (LLMs) offer a transformative path to automate this complex, interdisciplinary workflow through advanced code generation, tool usage, and agentic planning, the practical realization is significantly challenged by the current lack of a large-scale benchmark dedicated to automated quantitative backtesting, which hinders progress in this field. To bridge this critical gap, we introduce BacktestBench, the first large-scale benchmark for automated quantitative backtesting. Built from over 6 million real market records, it comprises 18,246 meticulously annotated question-answering pairs across four task categories: metrics calculation, ticker selection, strategy selection, and parameter confirmation. We also propose AutoBacktest, a robust multi-agent baseline that translates natural language strategies into reproducible backtests by coordinating a Summarizer for semantic factor extraction, a Retriever for validated SQL generation, and a Coder for Python backtesting implementation. Our evaluation on 23 mainstream LLMs, complemented by targeted ablations, identifies key factors that influence end-to-end performance and highlights the importance of grounded verification and standardized indicator representations.

Simply Stabilizing the Loop via Fully Looped Transformer

arXiv:2605.18797v2 Announce Type: replace-cross Abstract: Scaling model performance typically requires increasing model size. Looped Transformer offers a compelling alternative by iteratively reusing the same Transformer blocks, trading additional computation for improved performance without increasing parameter count or context length. Because the number of loop iterations can be adjusted at inference, it also provides a natural mechanism for balancing performance and test-time compute. However, Looped Transformer still suffers from training instability when the number of loop iterations increases. Our analysis reveals that this instability stems from two sources: gradient oscillation and residual explosion. To address these two problems, we propose the Fully Looped Transformer, which introduces two parameter-free modifications: (1) Fully Looped Architecture, which distributes inter-loop signals across all layers to mitigate residual explosion; (2) Attention Injection, which reuses the existing attention block to suppress gradient oscillation. These modifications stabilize training dynamics, enabling the Fully Looped Transformer to be trained stably up to 12 loop iterations, whereas other baseline looped models collapse in this regime. In milder settings where Looped Transformer does not collapse, Fully Looped Transformer still improves average downstream-task performance by up to 13.2\%. Overall, our experiments demonstrate that Fully Looped Transformer improves training stability, enhances downstream performance, and provides preliminary adaptability under different test-time compute budgets by varying loop iterations at inference.

Unlocking the Future of Hepatocellular Carcinoma Early Diagnosis: The Promise of Extracellular Vesicle Biomarkers

J Clin Transl Hepatol. 2026 Apr 28;14(4):462-477. doi: 10.14218/JCTH.2025.00589. Epub 2026 Apr 8.

ABSTRACT

Hepatocellular carcinoma (HCC) is one of the most prevalent and aggressive malignant tumors globally, with a notably low five-year survival rate. Its high mortality is largely attributed to challenges in early detection. Extracellular vesicles (EVs) are naturally occurring nanoparticles secreted by nearly all cell types and carry a diverse array of bioactive molecules, including proteins, nucleic acids (particularly non-coding RNAs), and lipids. EVs play pivotal roles in remodeling the tumor microenvironment and driving cancer progression through intercellular communication. Accumulating evidence has established that EVs are critically involved in the pathogenesis of HCC and are emerging as promising biomarkers for its early detection. With advances in EV isolation technologies, these vesicles have garnered considerable attention in the field of liquid biopsy for HCC. This review provides a comprehensive overview of the diagnostic potential of EV-derived biomarkers in HCC, including DNA, RNA, proteins, and lipids. Additionally, it discusses the advantages of integrating multi-omics approaches for HCC diagnosis. Furthermore, the review highlights the technical challenges in EV isolation and characterization, as well as the crucial role of reference genes in the standardization of EV data. These insights underscore the potential of EVs as novel, minimally invasive liquid biopsy biomarkers for the early diagnosis of HCC.

PMID:42181837 | PMC:PMC13195390 | DOI:10.14218/JCTH.2025.00589

Multi-omics integration identifies ribosome biogenesis-active macrophage subpopulation and its key gene GNL2 in driving liver hepatocellular carcinoma progression and mechanisms

Cancer Cell Int. 2026 May 14. doi: 10.1186/s12935-026-04330-2. Online ahead of print.

ABSTRACT

BACKGROUND: Liver hepatocellular carcinoma (LIHC) is a common malignancy, yet the core genes driving its progression and potential therapeutic targets remain insufficiently explored. Ribosome biogenesis (RB) is a critical biological process linked to various cancers; however, its systematic role in LIHC remains unclear.

METHODS: This study integrated LIHC single-cell RNA-Seq, bulk RNA-Seq, and spatial transcriptomic data with ribosome biogenesis-related gene sets to construct a single-cell atlas of LIHC. Weighted Gene Co-expression Network Analysis (WGCNA) was employed to characterize myeloid cell subsets. Furthermore, an LIHC prognostic risk model based on RB-related genes was developed using 117 machine-learning algorithm combinations. Key findings were subsequently corroborated through experimental validation and clinical sample analysis.

RESULTS: We identified a distinct macrophage subpopulation with high ribosome biogenesis activity, termed ribosome biogenesis-active macrophages (RAMs). These cells exhibited strong communication with inflammatory macrophages, potentially mediated by MIF-related receptor-ligand interactions. We further constructed an 8-gene prognostic model (PA2G4, GNL2, PWP1, DDX49, NOC4L, GDI2, CST7, and RCL1), which showed good predictive performance. Drug sensitivity analysis suggested that the high-risk group may be more responsive to several agents, including docetaxel. Among these genes, GNL2 was selected for further investigation. Elevated GNL2 expression was associated with increased stemness features in myeloid cells. Molecular docking analysis identified several candidate compounds with potential binding affinity to GNL2. Functionally, GNL2 knockdown in macrophages reduced TGF-β and TNF-α expression and was associated with decreased proliferation, migration, and invasion of LIHC cells.

CONCLUSION: We identified a highly active ribosome biogenesis-macrophage subpopulation (RAM), and constructed a robust risk model to aid in the diagnosis, prognosis, and treatment of LIHC. GNL2 is associated with increased expression of TGF-β and TNF-α and may contribute to LIHC progression.

PMID:42135716 | DOI:10.1186/s12935-026-04330-2

Sirt1 sustains Sonic hedgehog signaling to promote medulloblastoma progression through regulating Gli3 processing

Oncogene, Published online: 18 April 2026; doi:10.1038/s41388-026-03781-1

Sirt1 sustains Sonic hedgehog signaling to promote medulloblastoma progression through regulating Gli3 processing

Integrative fragmentomic and mutational signature profile of plasma cfDNA for early lung cancer detection

NPJ Precis Oncol. 2026 Apr 15. doi: 10.1038/s41698-026-01416-y. Online ahead of print.

ABSTRACT

Detecting lung cancer effectively in the general population is essential for optimizing treatment outcomes and improving the 5-year survival rate. While low-dose computed tomography (LDCT) is the current standard, it has limitations in broader populations. We developed a blood-based multi-omics model using whole-genome cell-free DNA (cfDNA) features to distinguish lung cancer from non-cancer individuals. This study included 1600 patients and an equal number of non-cancer controls, divided into training and validation cohorts. The model achieved an area under the curve (AUC) of 95.59% for the training cohort and 95.74% for the validation cohort. The model consistently performed well across various cancer stages and histological subtypes. To further validate the performance of the model, an external validation cohort was utilized. Notably, it also effectively differentiated non-cancer samples from cancer samples in the external validation cohort, with 85.9% sensitivity and 94.78% specificity. Importantly, in simulated population screenings, our ctDNA assay outperformed both LDCT and a previously established method. This suggests its potential utility in wider lung cancer screening programs, possibly complementing the LDCT approach. In conclusion, our ctDNA assay emerges as a promising and highly sensitive tool for the early detection and categorization of lung cancer.

PMID:41986614 | DOI:10.1038/s41698-026-01416-y

Correction: Steroid receptor coactivator-1 facilitates METTL3-mediated m6A modification by coactivating NF-κB and promotes the malignant progression of glioblastoma

Oncogene, Published online: 15 April 2026; doi:10.1038/s41388-026-03788-8

Correction: Steroid receptor coactivator-1 facilitates METTL3-mediated m6A modification by coactivating NF-κB and promotes the malignant progression of glioblastoma

AdaptFuse: Training-Free Sequential Preference Learning via Externalized Bayesian Inference

arXiv:2604.03925v1 Announce Type: cross Abstract: Large language models struggle to accumulate evidence across multiple rounds of user interaction, failing to update their beliefs in a manner consistent with Bayesian inference. Existing solutions require fine-tuning on sensitive user interaction data, limiting their applicability in privacy-conscious settings. We propose AdaptFuse, a training-free framework that externalizes probabilistic computation entirely from the LLM: a symbolic module maintains a Bayesian posterior over a discrete hypothesis set, while a frozen LLM contributes semantic reasoning via multi-sample Dirichlet aggregation. The two signals are combined through entropy-adaptive fusion, which automatically weights each source by its predictive confidence, shifting reliance from the LLM to the symbolic posterior as evidence accumulates. We evaluate across three domains: flight recommendation, hotel recommendation, and web shopping; on Gemma 2 9B, Llama 3 8B, and Qwen 2.5 7B. AdaptFuse consistently outperforms both prompting baselines and fine-tuned Bayesian Teaching models on all tasks, with accuracy improving monotonically over interaction rounds. These results demonstrate that principled inference-time algorithms can substitute for fine-tuning in personalized recommendation, without storing or training on sensitive user data. All the code and materials will be open-sourced.

Preserving Forgery Artifacts: AI-Generated Video Detection at Native Scale

arXiv:2604.04634v1 Announce Type: cross Abstract: The rapid advancement of video generation models has enabled the creation of highly realistic synthetic media, raising significant societal concerns regarding the spread of misinformation. However, current detection methods suffer from critical limitations. They rely on preprocessing operations like fixed-resolution resizing and cropping. These operations not only discard subtle, high-frequency forgery traces but also cause spatial distortion and significant information loss. Furthermore, existing methods are often trained and evaluated on outdated datasets that fail to capture the sophistication of modern generative models. To address these challenges, we introduce a comprehensive dataset and a novel detection framework. First, we curate a large-scale dataset of over 140K videos from 15 state-of-the-art open-source and commercial generators, along with Magic Videos benchmark designed specifically for evaluating ultra-realistic synthetic content. In addition, we propose a novel detection framework built on the Qwen2.5-VL Vision Transformer, which operates natively at variable spatial resolutions and temporal durations. This native-scale approach effectively preserves the high-frequency artifacts and spatiotemporal inconsistencies typically lost during conventional preprocessing. Extensive experiments demonstrate that our method achieves superior performance across multiple benchmarks, underscoring the critical importance of native-scale processing and establishing a robust new baseline for AI-generated video detection.

Discovering Failure Modes in Vision-Language Models using RL

arXiv:2604.04733v1 Announce Type: cross Abstract: Vision-language Models (VLMs), despite achieving strong performance on multimodal benchmarks, often misinterpret straightforward visual concepts that humans identify effortlessly, such as counting, spatial reasoning, and viewpoint understanding. Previous studies manually identified these weaknesses and found that they often stem from deficits in specific skills. However, such manual efforts are costly, unscalable, and subject to human bias, which often overlooks subtle details in favor of salient objects, resulting in an incomplete understanding of a model's vulnerabilities. To address these limitations, we propose a Reinforcement Learning (RL)-based framework to automatically discover the failure modes or blind spots of any candidate VLM on a given data distribution without human intervention. Our framework trains a questioner agent that adaptively generates queries based on the candidate VLM's responses to elicit incorrect answers. Our approach increases question complexity by focusing on fine-grained visual details and distinct skill compositions as training progresses, consequently identifying 36 novel failure modes in which VLMs struggle. We demonstrate the broad applicability of our framework by showcasing its generalizability across various model combinations.

ContextDrag: Precise Drag-Based Image Editing via Context-Preserving Token Injection and Position-Aligned Attention

arXiv:2512.08477v2 Announce Type: replace-cross Abstract: Drag-based image editing enables intuitive visual manipulation through point-based drag operations. Existing methods mainly rely on diffusion inversion or pixel-space warping with inpainting. However, inversion inherently introduces approximation errors that degrade texture fidelity, whereas rigid pixel-space operations discard semantic context and produce unnatural deformations. To address these issues, we introduce ContextDrag, to our knowledge the first framework that brings drag-based manipulation into the in-context image editing paradigm. By leveraging the in-context capabilities of editing models (e.g., FLUX-Kontext), ContextDrag enables precise drag editing without inversion or fine-tuning. Specifically, we first propose Context-preserving Token Injection (CTI), which injects VAE-encoded reference features into attention layers at spatially aligned target positions, guided by latent-space correspondences estimated directly from user-specified control points. By operating on clean, directly encoded features rather than noisy inversion outputs, CTI preserves rich texture details and enables precise drag control. Second, we propose Position-Aligned Attention (PAA) to eliminate interference caused by spatial displacement of reference features. PAA re-encodes positional embeddings of displaced reference tokens to match their target locations, and masks overlapping regions between source and destination to prevent conflicting features from degrading visual consistency. Experiments on DragBench-SR and DragBench-DR demonstrate that ContextDrag achieves SOTA editing accuracy and overall quality, and comprehensive ablations validate the effectiveness of each proposed component. Code will be publicly available.

GPA: Learning GUI Process Automation from Demonstrations

arXiv:2604.01676v2 Announce Type: replace-cross Abstract: GUI Process Automation (GPA) is a lightweight but general vision-based Robotic Process Automation (RPA), which enables fast and stable process replay with only a single demo. Addressing the fragility of traditional RPA and the non-deterministic risks of current vision language model-based GUI agents, GPA introduces three core benefits: (1) Robustness via Sequential Monte Carlo-based localization to handle rescaling and detection uncertainty; (2) Deterministic and Reliability safeguarded by readiness calibration; and (3) Privacy through fast, fully local execution. This approach delivers the adaptability, robustness, and security required for enterprise workflows. It can also be used as an MCP/CLI tool by other agents with coding capabilities so that the agent only reasons and orchestrates while GPA handles the GUI execution. We conducted a pilot experiment to compare GPA with Gemini 3 Pro (with CUA tools) and found that GPA achieves higher success rate with 10 times faster execution speed in finishing long-horizon GUI tasks.

Multi-omics integration and machine learning reveal gut-immune signatures in idiopathic pulmonary fibrosis: insights from bulk RNA-seq, single-cell profiles, spatial transcriptomics, and experimental validation

Front Immunol. 2026 Mar 19;17:1730289. doi: 10.3389/fimmu.2026.1730289. eCollection 2026.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease with limited treatment options and a poor prognosis. Recent studies suggest a critical role for the gut-immune-lung axis in IPF, yet the underlying molecular mechanisms remain unclear.

METHODS: The current study performed in silico multi-omics integration of publicly available datasets, including bulk RNA-seq, single-cell and spatial transcriptomics, as well as peripheral blood multi-omics data to uncover key molecular signatures in IPF. Furthermore, machine learning techniques were utilized to identify core genes, whereas functional analyses and Mendelian randomization were conducted to evaluate the causal relationships among gut microbiota, immune cells, and IPF. Additionally, experimental validation using qPCR and ELISA assays was conducted in vitro, in vivo, and in patient plasma to confirm the expression patterns of key genes.

RESULTS: Across integrated public bulk, single-cell, spatial, and blood multi-omics, CXCL13, IL33, TLR4, and IGF1 were identified as core IPF genes consistently linked to immune infiltration and fibrotic remodeling. Deconvolution, scRNA-seq, and spatial mapping localized their dysregulation to fibroblasts and immune compartments (notably B-cell, macrophage, and mast-cell axes), highlighting fibroblast-immune crosstalk in fibrotic foci. A four-gene model robustly distinguished IPF from controls across cohorts. Mendelian randomization supported a gut-immune-lung axis, indicating causal effects of specific gut taxa on IPF risk via immune phenotypes. qPCR/ELISA in TGF-β1-stimulated fibroblasts, bleomycin mouse lungs, and patient plasma corroborated upregulation of IL33, CXCL13, IGF1 and downregulation of TLR4. Drug-signature reversal nominated cucurbitacin I and temsirolimus; molecular docking was performed as a preliminary in silico, computer-simulation-based assessment of potential ligand-protein interactions between these compounds and the four core targets.

CONCLUSION: This study provides new insights into the importance of gut-immune-lung axis in IPF and identifies CXCL13, IL33, TLR4, and IGF1 as diagnostic signatures and therapeutic targets. By integrating public multi-omics resources with experimental validation, our findings offer a foundation for future diagnostic and treatment strategies aimed at modulating the gut microbiota and immune system in IPF.

PMID:41939867 | PMC:PMC13043422 | DOI:10.3389/fimmu.2026.1730289

Multi-omics integration and machine learning reveal gut-immune signatures in idiopathic pulmonary fibrosis: insights from bulk RNA-seq, single-cell profiles, spatial transcriptomics, and experimental validation

Front Immunol. 2026 Mar 19;17:1730289. doi: 10.3389/fimmu.2026.1730289. eCollection 2026.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease with limited treatment options and a poor prognosis. Recent studies suggest a critical role for the gut-immune-lung axis in IPF, yet the underlying molecular mechanisms remain unclear.

METHODS: The current study performed in silico multi-omics integration of publicly available datasets, including bulk RNA-seq, single-cell and spatial transcriptomics, as well as peripheral blood multi-omics data to uncover key molecular signatures in IPF. Furthermore, machine learning techniques were utilized to identify core genes, whereas functional analyses and Mendelian randomization were conducted to evaluate the causal relationships among gut microbiota, immune cells, and IPF. Additionally, experimental validation using qPCR and ELISA assays was conducted in vitro, in vivo, and in patient plasma to confirm the expression patterns of key genes.

RESULTS: Across integrated public bulk, single-cell, spatial, and blood multi-omics, CXCL13, IL33, TLR4, and IGF1 were identified as core IPF genes consistently linked to immune infiltration and fibrotic remodeling. Deconvolution, scRNA-seq, and spatial mapping localized their dysregulation to fibroblasts and immune compartments (notably B-cell, macrophage, and mast-cell axes), highlighting fibroblast-immune crosstalk in fibrotic foci. A four-gene model robustly distinguished IPF from controls across cohorts. Mendelian randomization supported a gut-immune-lung axis, indicating causal effects of specific gut taxa on IPF risk via immune phenotypes. qPCR/ELISA in TGF-β1-stimulated fibroblasts, bleomycin mouse lungs, and patient plasma corroborated upregulation of IL33, CXCL13, IGF1 and downregulation of TLR4. Drug-signature reversal nominated cucurbitacin I and temsirolimus; molecular docking was performed as a preliminary in silico, computer-simulation-based assessment of potential ligand-protein interactions between these compounds and the four core targets.

CONCLUSION: This study provides new insights into the importance of gut-immune-lung axis in IPF and identifies CXCL13, IL33, TLR4, and IGF1 as diagnostic signatures and therapeutic targets. By integrating public multi-omics resources with experimental validation, our findings offer a foundation for future diagnostic and treatment strategies aimed at modulating the gut microbiota and immune system in IPF.

PMID:41939867 | PMC:PMC13043422 | DOI:10.3389/fimmu.2026.1730289

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