Excavating Podocyte-Protective Targets of phloroglucinol-terpene hybrids Utilizing AI Models and Omics Analysis

作者：Ting Chen, Xiaoyan Liu, Juan Zhu, Xinting Zhang, Jianhui Zhang, Hongping Yu, Ziyan Xu, Dingyan Wang, Yao‐Bin Zhu, Feisheng Zhong, Luo Jiewei · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2025 · DOI：10.1101/2025.02.22.639610 · 被引用次数：2 · 研究领域：Hops Chemistry and Applications、Plant Pathogens and Resistance、Gene Regulatory Network Analysis

Abstract Lupus nephritis (LN) is a multifactorial autoimmune inflammatory disorder, with podocyte dysfunction or structural abnormalities playing a pivotal role in its pathogenesis. Eucalyptus leaves, traditionally employed in folk medicine, have demonstrated notable efficacy in managing non-infectious inflammations. Eucarbwenstols D (R14) is a novel phloroglucinol-terpene that has been isolated from Eucalyptus robusta . To further refine potential targets, we utilized an AI scoring system and successfully identified the epidermal growth factor receptor (EGFR) as the novel target of R14. This discovery was built upon the foundation of transcriptome and connectivity mapping (CMap) analysis. Molecular docking and molecular dynamics simulations were employed to analyze the interaction between R14 and EGFR, surface plasmon resonance (SPR) and homogeneous time-resolved fluorescence (HTRF) assays were utilized to accurately quantify the binding affinity between R14 and EGFR. Western blot (WB) and immunofluorescence assays were then conducted to explore the downstream signaling pathways initiated by EGFR, specifically the PI3K/AKT/mTOR pathway. These assays demonstrated that R14 modulates the expression of apoptotic proteins Bax and Bcl-2 through this pathway, thereby exerting a protective effect on podocytes from undergoing apoptosis. The modulation of key podocyte proteins, nephrin and podocin, further substantiates this protective effect. Overall, we have applied a novel AI algor...