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Isoginkgetin as a novel USP8 inhibitor discovered by structure-based virtual screening exerts anticancer effects in
Bingjin Hu1, Ying Liu2, Zhuoyue Zhao3
1College of Pharmacy, Dalian Medical University, Dalian, 116044, China.
Abstract:
Ubiquitin-specific protease 8 (USP8) gene has been identified as being significantly amplified and overexpressed in Ovarian carcinoma (OC), and thus led to unfavorable clinical outcomes, implying that inhibition of USP8 may be a therapeutic strategy for OC. Herein, a structure-based discovery and bioassays were conducted to identify novel inhibitors of USP8. we employed a novel platform that integrates docking/molecular dynamics (MD) simulation/binding free energy calculations/root-mean-square deviation (RMSD)/USP8 enzyme activity assay to screen a library of bioactive compounds including 30000 compounds. we identified that Isoginkgetin exhibited promising inhibitory activity on USP8 with an IC50 value of 12.68 μM. Moreover, Isoginkgetin could significantly inhibit OC cell growth by suppressing cell proliferation and reducing colony formation, and promoting Fe2+ accumulation, ROS production, thereby triggering cell death. These suppressive effects were successfully reversed by Ferrostatin-1 (Fer-1). Mechanistically, Isoginkgetin decreased USP8 levels, leading to ubiquitin degradation and glutathione peroxidase 4 (GPX4) instability, and it stimulated ferroptosis. Ultimately, our results support Isoginkgetin as a potent inhibitor of USP8, the inhibition of which may be a promising therapeutic strategy for OC.
Insights
Isoginkgetin inhibits USP8, a target in ovarian cancer. This compound suppresses cancer cell growth and triggers cell death by promoting ferroptosis, offering a potential new therapy for ovarian carcinoma.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Ubiquitin-specific protease 8 (USP8) is overexpressed in ovarian carcinoma (OC), correlating with poor patient outcomes.
- USP8 inhibition presents a potential therapeutic avenue for OC treatment.
Purpose of the Study:
- To identify novel USP8 inhibitors using structure-based drug discovery.
- To evaluate the efficacy of identified inhibitors in OC models.
Main Methods:
- A computational platform integrating docking, molecular dynamics (MD) simulations, and binding free energy calculations was used to screen 30,000 compounds.
- USP8 enzyme activity assays, OC cell proliferation assays, colony formation assays, and ferroptosis analysis were performed.
- Mechanistic studies involved assessing USP8 levels, protein degradation, and ferroptosis markers.
Main Results:
- Isoginkgetin demonstrated significant USP8 inhibitory activity (IC50 = 12.68 μM).
- Isoginkgetin suppressed OC cell proliferation, colony formation, and induced cell death via ferroptosis (indicated by Fe2+ accumulation and ROS production).
- Ferrostatin-1 (Fer-1) reversed Isoginkgetin's suppressive effects, confirming ferroptosis involvement. Isoginkgetin reduced USP8 levels, leading to GPX4 instability and ferroptosis.
Conclusions:
- Isoginkgetin is a potent USP8 inhibitor with significant anti-OC activity.
- USP8 inhibition by Isoginkgetin triggers ferroptosis, presenting a promising therapeutic strategy for ovarian carcinoma.
