Hypericum monogynum extract inhibits human aortic valve interstitial cell calcification by interfering with the EGFR/PI3K/AKT signaling pathway

Abstract

Calcific aortic valve disease (CAVD) is a serious heart valve condition with increasing global prevalence. Currently, transcatheter aortic valve implantation (TAVI) or surgical aortic valve replacement (SAVR) represents the only available treatment strategy, as no pharmaceutical therapies for CAVD are approved. The aim of this study was to identify compounds capable of inhibiting osteogenic differentiation of human aortic valve interstitial cells (hVICs), a process critically implicated in CAVD pathogenesis, and to elucidate the underlying molecular mechanism. From an in-house library of 88 compounds screened via dot-blotting, we identified chipericumin D, a natural compound extracted from Hypericum monogynum L., as a candidate exhibiting potent inhibitory activity against hVIC osteogenic differentiation. Network pharmacology analysis, molecular docking, drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), and surface plasmon resonance (SPR) collectively demonstrated direct binding of chipericumin D to the epidermal growth factor receptor (EGFR). Furthermore, chipericumin D suppressed activation of the EGFR/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway in hVICs cultured under osteogenic medium (OM) conditions. These findings indicate that chipericumin D is a promising therapeutic candidate for CAVD, and provide preliminary evidence that EGFR constitutes a novel molecular target for CAVD intervention.

Keywords

Hypericum monogynum / Calcific aortic valve disease / Drug screening / Dot-blotting / Natural compound / EGFR

Funding

This work was supported by the National Key R&D Program of China (Nos. 2021YFA1101900 and 2021YFA0910500), the National Natural Science Foundation of China (Nos. 82100303, 82273811, 22577033, 82470423, and 82404822), the Hubei Provincial Natural Science Foundation Projects (Nos. JCZRYB2025-00142 and 2024AFA028), the Wuhan International Science and Technology Cooperation Project (No. 2025071204030392), the Fundamental Research Funds for the Central Universities (HUST: Nos. YCJJ20252429 and 2025BRA015), the National Program for Support of Top-notch Young Professionals (No. 0106514050), the Guangdong Basic and Applied Basic Research Foundation (No. 2023A1515110763), the China Postdoctoral Science Foundation (No. 2023M742415), the Shenzhen Science and Technology Program (No. JCYJ20220818101806014), and the Team-based Medical Science Research Program (No. 2024YZZ11).

Supporting information

Supplementary data associated with this article can bere-quested by sending E-mail to the corresponding authors.

Declaration of generative AI and AI-assisted technologies in the writing process

In the writing process, we used GPT-3.5 for language translation. Additionally, we affirm that we did not rely on Generative AI or AI-assisted technologies to generate any original thoughts or content, and we thoroughly reviewed the article and take complete responsibility for its content.

Acknowledgements

Thanks for the technical support by the Medical Subcenter of HUST Analytical & Testing Center.

Declaration of competing interest

These authors declare no conflict of interest.

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