Integrating UHPLC-QE-MS and Bioinformatics with Experimental Validation Reveals MAPK/FOS-Mediated Podocyte Apoptosis as the Key Mechanism of Alpiniae oxyphyllae and Saposhnikovia divaricata in Treating Diabetic Kidney Disease

Wang, Xian; Zhang, Lin; Tang, Rongxin; Zhang, Wenlong; Xie, Yiqiang; Li, Kai

doi:10.3390/ph18101449

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Integrating UHPLC-QE-MS and Bioinformatics with Experimental Validation Reveals MAPK/FOS-Mediated Podocyte Apoptosis as the Key Mechanism of Alpiniae oxyphyllae and Saposhnikovia divaricata in Treating Diabetic Kidney Disease

by

Xian Wang

^†,

Lin Zhang

^†,

Rongxin Tang

,

Wenlong Zhang

,

Yiqiang Xie

^* and

Kai Li

^*

School of Traditional Chinese Medicine, Hainan Medical University, Haikou 571199, China

^*

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Pharmaceuticals 2025, 18(10), 1449; https://doi.org/10.3390/ph18101449 (registering DOI)

Submission received: 27 July 2025 / Revised: 27 August 2025 / Accepted: 25 September 2025 / Published: 27 September 2025

(This article belongs to the Section Pharmacology)

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Abstract

Background:Alpiniae oxyphyllae-Saposhnikovia divaricata (AS), a traditional Chinese dietary supplement, exhibits potential therapeutic effects against diabetic kidney disease (DKD), though its active compounds and mechanisms require elucidation. Methods: Animal experiments integrated with UHPLC-QE-MS, bioinformatics, and experimental validation were employed to investigate AS’s pharmacodynamic basis against DKD. Results: Thirty-nine compounds were identified in AS, including four key flavonoids (daidzein, kaempferol, tectoridin, baicalin). Bioinformatics screening revealed 516 potential AS targets from PubChem/TCMSP/ETCM databases. Analysis of the GEO dataset (GSE30529) identified 482 DKD-related differentially expressed genes (DEGs). Venny 2.1 analysis yielded 42 co-DEGs and 6 co-core DEGs. Functional enrichment (GO/KEGG/GSEA) demonstrated AS’s modulation of apoptosis and extracellular matrix (ECM) pathways via these DEGs. ROC profiling and renal single-cell sequencing highlighted FOS as a specific regulator of podocyte apoptosis in DKD. Molecular docking confirmed stable binding between the four flavonoids and FOS. Experimentally, AS significantly suppressed expression of ECM-related proteins (Col-IV, LN, IL-6, IL-17) and pro-apoptotic proteins (Bax, Caspase-3), while restoring anti-apoptotic Bcl-2 levels and inhibiting phosphorylation of MEK4, JNK1, c-Jun, and FOS in DKD mice. Conclusion: This study elucidates that AS alleviates DKD by inhibiting the MAPK/FOS pathway, thereby attenuating podocyte apoptosis and ECM accumulation. These findings establish a foundation for targeted AS therapy in DKD.

Keywords: diabetic kidney disease; Alpiniae oxyphyllae-Saposhnikoviae divaricat a; podocyte apoptosis; MAPK/FOS signaling pathway

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MDPI and ACS Style

Wang, X.; Zhang, L.; Tang, R.; Zhang, W.; Xie, Y.; Li, K. Integrating UHPLC-QE-MS and Bioinformatics with Experimental Validation Reveals MAPK/FOS-Mediated Podocyte Apoptosis as the Key Mechanism of Alpiniae oxyphyllae and Saposhnikovia divaricata in Treating Diabetic Kidney Disease. Pharmaceuticals 2025, 18, 1449. https://doi.org/10.3390/ph18101449

AMA Style

Wang X, Zhang L, Tang R, Zhang W, Xie Y, Li K. Integrating UHPLC-QE-MS and Bioinformatics with Experimental Validation Reveals MAPK/FOS-Mediated Podocyte Apoptosis as the Key Mechanism of Alpiniae oxyphyllae and Saposhnikovia divaricata in Treating Diabetic Kidney Disease. Pharmaceuticals. 2025; 18(10):1449. https://doi.org/10.3390/ph18101449

Chicago/Turabian Style

Wang, Xian, Lin Zhang, Rongxin Tang, Wenlong Zhang, Yiqiang Xie, and Kai Li. 2025. "Integrating UHPLC-QE-MS and Bioinformatics with Experimental Validation Reveals MAPK/FOS-Mediated Podocyte Apoptosis as the Key Mechanism of Alpiniae oxyphyllae and Saposhnikovia divaricata in Treating Diabetic Kidney Disease" Pharmaceuticals 18, no. 10: 1449. https://doi.org/10.3390/ph18101449

APA Style

Wang, X., Zhang, L., Tang, R., Zhang, W., Xie, Y., & Li, K. (2025). Integrating UHPLC-QE-MS and Bioinformatics with Experimental Validation Reveals MAPK/FOS-Mediated Podocyte Apoptosis as the Key Mechanism of Alpiniae oxyphyllae and Saposhnikovia divaricata in Treating Diabetic Kidney Disease. Pharmaceuticals, 18(10), 1449. https://doi.org/10.3390/ph18101449

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Integrating UHPLC-QE-MS and Bioinformatics with Experimental Validation Reveals MAPK/FOS-Mediated Podocyte Apoptosis as the Key Mechanism of Alpiniae oxyphyllae and Saposhnikovia divaricata in Treating Diabetic Kidney Disease

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