2. Academic Validation
  3. USP7 inhibitor P5091 enhances the antitumor efficacy of vemurafenib in BRAFV600E-mutant thyroid cancer via ferroptosis

USP7 inhibitor P5091 enhances the antitumor efficacy of vemurafenib in BRAFV600E-mutant thyroid cancer via ferroptosis

  • Biochem Pharmacol. 2026 Jan;243(Pt 2):117522. doi: 10.1016/j.bcp.2025.117522.
Chenchen Hu 1,  Wenzhi Tian 2,  Yun Tang 1,  Peiran Wang 3,  Tiantian Kuan 3,  Wei Wei 1,  Dong Chen 4,  Peng Li 5,  Xi Su 6
Affiliations

Affiliations

  • 1 Department of Thyroid and Breast Surgery, Peking University Shenzhen Hospital, Shenzhen 518036 Guangdong Province, China.
  • 2 Department of Thyroid and Breast Surgery, Peking University Shenzhen Hospital, Shenzhen 518036 Guangdong Province, China; Shenzhen University Clinical Medical Academy Center, Shenzhen University, Shenzhen 518060 Guangdong Province, China.
  • 3 Department of Thyroid and Breast Surgery, Peking University Shenzhen Hospital, Shenzhen 518036 Guangdong Province, China; Department of Thyroid and Breast Surgery, Peking University Shenzhen Hospital, PKU-Shenzhen Clinical Institute of Shantou University Medical College, Shenzhen 518036 Guangdong Province, China.
  • 4 Department of Thyroid and Breast Surgery, Peking University Shenzhen Hospital, Shenzhen 518036 Guangdong Province, China. Electronic address: [email protected].
  • 5 Department of Thyroid and Breast Surgery, Peking University Shenzhen Hospital, Shenzhen 518036 Guangdong Province, China. Electronic address: [email protected].
  • 6 Department of Thyroid and Breast Surgery, Peking University Shenzhen Hospital, Shenzhen 518036 Guangdong Province, China. Electronic address: [email protected].
PMID: 41207567 DOI: 10.1016/j.bcp.2025.117522
Abstract

Resistance to the BRAF inhibitor vemurafenib (PLX4032) limits its efficacy in thyroid Cancer. Ubiquitin-specific peptidase 7 (USP7), a key regulator of oncogenic signaling, and USP7 Inhibitor may help overcome drug resistance. This study investigated the combined efficacy of PLX4032 and the USP7 Inhibitor P5091 in BRAFV600E-mutant thyroid Cancer. Bioinformatics showed that USP7 and Integrin subunit beta 3 (ITGB3), a MAPK/PI3K pathway gene, may jointly mediate resistance. In thyroid Cancer cell lines, the combination treatment significantly reduced viability, proliferation, colony formation, migration, and invasion versus monotherapy. Moreover, the combination treatment can reduce viability and induce cell death in thyroid Cancer organoids. Given USP7's role in oxidative stress and Ferroptosis, we examined its involvement and found that P5091 induced Ferroptosis via Reactive Oxygen Species (ROS) elevation, Glutathione Peroxidase 4 (GPX4) downregulation, and elevated lipid peroxidation. These findings demonstrate that USP7 inhibition by P5091 enhances PLX4032 efficacy by promoting tumor suppression and Ferroptosis in BRAFV600E-mutant thyroid Cancer, offering a promising strategy to overcome resistance.

Keywords

BRAF(V600E); Combination therapy; Organoid; P5091; Thyroid cancer; Vemurafenib.

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