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AI-driven pipeline discovers ombuin as a novel M1 macrophage polarization inhibitor for sepsis treatment

Shu-chen Gong1,2,3, Lan Jiang1, Qi-xiu Li1,4, Chen Yang1, Le Yu1,2,3, Shu-ying Lv1, Guang Yang1, Zhao-xu Yang1,2,3, Han Huang1, Yu-ming Hu1, Xiao-yu Chen1, Hao-yu Zhang5, Bo Yang1,6, Qiao-jun He1,4,7,8, Qin-jie Weng1,2,3,7,9, Jin-cheng Wang1,2,3
1 Center for Drug Safety Evaluation and Research, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310007, China
2 Taizhou Institute of Zhejiang University, Zhejiang University, Taizhou 318000, China
3 3Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
4 ZJU-Xinchang Joint Innovation Center (TianMu Laboratory)), Xinchang 312500, China
5 Institute of Intelligent Transportation Systems, College of Civil Engineering and Architecture, Zhejiang University, Hangzhou 310007, China
6 School of Medicine, Hangzhou City University, Hangzhou 310015, China
7 The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
8 Department of Pharmaceutical and Translational Toxicology, Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou 310058, China
9 Institute of Fundamental and Transdisciplinary Research Zhejiang University, Zhejiang University, Hangzhou 310058, China
Correspondence to: Qin-jie Weng: wengqinjie@zju.edu.cn, Jin-cheng Wang: wangjincheng@zju.edu.cn,
DOI: 10.1038/s41401-026-01752-6
Received: 18 August 2025
Accepted: 6 January 2026
Advance online: 24 February 2026

Abstract

Sepsis is a life-threatening condition driven by dysregulated immune responses to infection with excessive M1 macrophage polarization-driven cytokine storm which plays a key role in the early progression of sepsis. Targeting macrophage polarization represents a promising therapeutic strategy to improve sepsis outcomes. Conventional drug discovery is hampered by high costs, long timelines and low success rates, posing significant challenges to the identification of novel M1 polarization inhibitors. In this study we constructed a novel transformer-variational autoencoder (TVAE) that integrated complementary molecular fingerprints (extended-connectivity fingerprints, ECFP; molecular ACCess system keys, MACCS keys; 4-point pharmacophore fingerprints, 4-PP) into probabilistic latent distributions to screen for M1-polarization inhibitors. From 5516 natural products, TVAE combined with experimental validation identified ombuin as the top candidate. In vitro, ombuin (10 μM) potently suppressed LPS-induced M1 polarization and pro-inflammatory cytokine (IL-6, TNF-α) release. In cecal ligation and puncture (CLP)-induced mouse sepsis model, administration of ombuin (15, 45 mg/kg, i.p.) significantly improved survival and ameliorated systemic inflammation by modulating the balance of M1/M2 macrophage polarization. By performing LiP-MS assay, we demonstrated that ombuin bound to and activated aldehyde dehydrogenase 2 (ALDH2), thereby suppressing NF-κB p65 nuclear translocation, a key event underlying NF-κB-driven M1 macrophage polarization. Collectively, our AI-driven pipeline efficiently discovers immunomodulatory agents and positions ombuin as a promising lead for sepsis therapy.
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