Resveratrol ameliorates sepsis-induced immune dysfunction by targeting GADD45A to maintain hematopoietic stem cell homeostasis: A predictive study integrating ensemble machine learning, single-cell transcriptomics, and molecular dynamics simulation.
为探究白藜芦醇（RES）通过GADD45A介导的造血调控通路改善脓毒症相关免疫功能障碍的潜在药理机制，本研究整合了网络药理学、集成机器学习和单细胞转录组学。采用涵盖113种算法组合的穷举框架结合SHAP可解释性分析筛选核心靶点。运用CIBERSORT量化脓毒症诱导的免疫微环境改变。利用单细胞RNA测序（scRNA-seq）定位枢纽靶点的细胞特异性分布，同时采用scTenifoldKnk虚拟敲除算法评估其对造血和免疫谱系的系统性转录影响。最后，通过分子对接和100 ns分子动力学（MD）模拟评估RES与候选靶点的结合亲和力及热力学稳定性。研究鉴定出四个枢纽基因（JAK1、GADD45A、MAPK14和ARG1），其中GADD45A具有最高的预测权重（SHAP：0.0350）和稳健的诊断性能。免疫浸润分析揭示了脓毒症中显著的髓系偏移。单细胞分辨率显示GADD45A特异性富集于髓系亚群，其表达与造血干细胞（HSCs）向髓系谱系的分化轨迹高度相关。虚拟敲除模拟预测GADD45A功能受损可能扰动HSC-G-CSF和前B细胞的转录模式，可能通过削弱对警报素S100A9的负向调控而加剧炎症反应。尽管RES与GADD45A的对接评分在核心基因中并非最高，但MD模拟证实在显式溶剂中具有更优的热力学稳定性，为其作为药理靶点提供了预测性结构基础。本研究提示白藜芦醇可能通过调控GADD45A介导的HSC转录程序来缓解脓毒症相关髓系偏移和免疫功能障碍。这些预测性发现为白藜芦醇在维持造血稳态中的应用提供了新的分子线索和潜在机制。
To investigate the potential pharmacological mechanisms of resveratrol (RES) in ameliorating sepsis-associated immune dysfunction via the GADD45A-mediated hematopoietic regulatory pathway. This study integrated network pharmacology, ensemble machine learning, and single-cell transcriptomics. Core targets were screened using an exhaustive framework of 113 algorithm combinations coupled with SHAP interpretability analysis. CIBERSORT was employed to quantify sepsis-induced alterations in the immune microenvironment. Single-cell RNA sequencing (scRNA-seq) was used to localize cell-specific distribution of hub targets, while the scTenifoldKnk virtual knockout algorithm assessed their systematic transcriptional impacts on hematopoietic and immune lineages. Finally, molecular docking and 100-ns molecular dynamics (MD) simulations were performed to evaluate the binding affinity and thermodynamic stability of RES with candidate targets. Four hub genes (JAK1, GADD45A, MAPK14, and ARG1) were identified, with GADD45A exhibiting the highest predictive weight (SHAP: 0.0350) and robust diagnostic performance. Immune infiltration analysis revealed a significant myeloid shift in sepsis. Single-cell resolution indicated that GADD45A was specifically enriched in myeloid subclusters, and its expression was highly correlated with the differentiation trajectory of hematopoietic stem cells (HSCs) toward the myeloid lineage. Virtual knockout simulations predicted that GADD45A impairment might perturb transcriptional patterns in HSC-G-CSF and pre-B cells, potentially exacerbating inflammatory responses by weakening the negative regulation of the alarmin S100A9. Although the docking score of RES with GADD45A was not the highest among core genes, MD simulations confirmed superior thermodynamic stability in explicit solvent, providing a predictive structural basis for its role as a pharmacological target. This study suggests that resveratrol potentially alleviates sepsis-associated myeloid bias and immune dysfunction by modulating GADD45A-mediated HSC transcriptional programs. These predictive findings offer novel molecular clues and potential mechanisms for the application of resveratrol in maintaining hematopoietic homeostasis.
Tong Liu, Chenqu Lyu, Xin Wang. Resveratrol ameliorates sepsis-induced immune dysfunction by targeting GADD45A to maintain hematopoietic stem cell homeostasis: A predictive study integrating ensemble machine learning, single-cell transcriptomics, and molecular dynamics simulation.. International immunopharmacology. 2026; doi:10.1016/j.intimp.2026.116470.
Tong Liu, Chenqu Lyu, Xin Wang (2026). Resveratrol ameliorates sepsis-induced immune dysfunction by targeting GADD45A to maintain hematopoietic stem cell homeostasis: A predictive study integrating ensemble machine learning, single-cell transcriptomics, and molecular dynamics simulation.. International immunopharmacology. https://doi.org/10.1016/j.intimp.2026.116470
Tong Liu, Chenqu Lyu, Xin Wang. Resveratrol ameliorates sepsis-induced immune dysfunction by targeting GADD45A to maintain hematopoietic stem cell homeostasis: A predictive study integrating ensemble machine learning, single-cell transcriptomics, and molecular dynamics simulation.[J]. International immunopharmacology, 2026 doi:10.1016/j.intimp.2026.116470.
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