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Article

Multi-Pathway Mechanisms of Engeletin in Ischemic Stroke: A Comprehensive Study Based on Network Pharmacology, Machine Learning, and Immune Infiltration Analysis

by
Huiming Xue
1,
Yuchen Wen
1,
Jiahui Yang
1,
Yue Zhang
1,
Chang Jin
1,
Bing Li
1,
Yongxing Ai
2,
Meizhu Zheng
3,*,
Boge Wen
4,* and
Kai Song
3
1
College of Life Sciences, Changchun Normal University, Changchun 130032, China
2
College of Animal Science, Jilin University, 5333 Xi’an Road, Changchun 130062, China
3
Central Laboratory, Changchun Normal University, Changchun 130032, China
4
College of Computer Science & Engineering, Changchun University of Technology, Changchun 130012, China
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(23), 11446; https://doi.org/10.3390/ijms262311446
Submission received: 28 September 2025 / Revised: 15 November 2025 / Accepted: 18 November 2025 / Published: 26 November 2025
(This article belongs to the Special Issue The Anti-Inflammatory and Antioxidant Potential of Phytochemicals)
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Abstract

Ischemic stroke (IS) is a leading cause of mortality and long-term disability, underpinned by complex molecular mechanisms, such as oxidative stress, neuroinflammation, and apoptosis. The flavonoid Engeletin exhibits promising neuroprotective properties, but its mechanism of action remains largely unknown. In this study, we employed a systems biology approach, combined with artificial intelligence (AI), to uncover the multitarget mechanisms of Engeletin in IS. Potential targets were predicted using SwissTargetPrediction and PharmMapper and were found to intersect with IS-related genes from multiple disease databases. Functional enrichment analyses (GO/KEGG) revealed significant involvement in three classical neuroprotective pathways: PI3K-Akt-mTOR/Caspase/BCL2 (anti-apoptotic), TLR4/NF-κB (anti-inflammatory), and NRF2/KEAP1/HO-1 (antioxidant). Notably, we integrated six machine learning models (RF, SVM, GLM, KNN) to identify robust IS-specific biomarkers from the GSE22255 transcriptomic database. We used CIBERSORTx to characterize immune cell infiltration patterns in IS, revealing elevated populations of CD8+ T cells, M0 macrophages, and other PBMC-derived immune cells, suggesting the presence of an immunologically dynamic microenvironment. Molecular docking predicted favorable binding affinities of Engeletin to core targets (e.g., EGFR, IGF1R, KEAP1, JAK2). Finally, in vitro experiments using a Na2S2O4-induced PC12 cell model confirmed Engeletin’s efficacy in reducing oxidative stress, modulating calcium overload, and regulating apoptosis- and inflammation-related genes. Overall, our study establishes a comprehensive pharmacological mechanistic framework for Engeletin in combating IS and reveals the multitarget and multi-pathway neuroprotective mechanisms, thus providing preliminary support for using Engeletin in combating ischemic stroke.
Keywords: Engeletin; ischemic stroke; network pharmacology; machine learning; neuroprotection; immune profiling analysis Engeletin; ischemic stroke; network pharmacology; machine learning; neuroprotection; immune profiling analysis

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MDPI and ACS Style

Xue, H.; Wen, Y.; Yang, J.; Zhang, Y.; Jin, C.; Li, B.; Ai, Y.; Zheng, M.; Wen, B.; Song, K. Multi-Pathway Mechanisms of Engeletin in Ischemic Stroke: A Comprehensive Study Based on Network Pharmacology, Machine Learning, and Immune Infiltration Analysis. Int. J. Mol. Sci. 2025, 26, 11446. https://doi.org/10.3390/ijms262311446

AMA Style

Xue H, Wen Y, Yang J, Zhang Y, Jin C, Li B, Ai Y, Zheng M, Wen B, Song K. Multi-Pathway Mechanisms of Engeletin in Ischemic Stroke: A Comprehensive Study Based on Network Pharmacology, Machine Learning, and Immune Infiltration Analysis. International Journal of Molecular Sciences. 2025; 26(23):11446. https://doi.org/10.3390/ijms262311446

Chicago/Turabian Style

Xue, Huiming, Yuchen Wen, Jiahui Yang, Yue Zhang, Chang Jin, Bing Li, Yongxing Ai, Meizhu Zheng, Boge Wen, and Kai Song. 2025. "Multi-Pathway Mechanisms of Engeletin in Ischemic Stroke: A Comprehensive Study Based on Network Pharmacology, Machine Learning, and Immune Infiltration Analysis" International Journal of Molecular Sciences 26, no. 23: 11446. https://doi.org/10.3390/ijms262311446

APA Style

Xue, H., Wen, Y., Yang, J., Zhang, Y., Jin, C., Li, B., Ai, Y., Zheng, M., Wen, B., & Song, K. (2025). Multi-Pathway Mechanisms of Engeletin in Ischemic Stroke: A Comprehensive Study Based on Network Pharmacology, Machine Learning, and Immune Infiltration Analysis. International Journal of Molecular Sciences, 26(23), 11446. https://doi.org/10.3390/ijms262311446

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