Ebselen's role in overcoming cisplatin resistance in colorectal Cancer via SQSTM1 ubiquitination modulation
- Int Immunopharmacol. 2026 Jul 15:181:116705. doi: 10.1016/j.intimp.2026.116705.
- 1. The First Clinical College, Jinan University, Guangzhou 510630, China; Department of Surgical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233004, China.
- 2. Department of General Surgery, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233004, China.
- 3. Department of Surgical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233004, China.
- 4. Department of Radiation Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233004, China.
- 5. Department of Surgical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233004, China. Electronic address: [email protected].
- 6. The First Clinical College, Jinan University, Guangzhou 510630, China; Department of General Surgery, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233004, China. Electronic address: [email protected].
Cisplatin resistance severely limits chemotherapy efficacy in colorectal Cancer (CRC). Although Ebselen has antitumor potential, its role in reversing cisplatin resistance remains unclear. Here, we combined in vitro/in vivo assays with scRNA-seq and spatial transcriptomics to evaluate Ebselen in cisplatin-resistant CRC. In HCT116/DDP cells, Ebselen inhibited proliferation, migration and invasion, promoted Apoptosis, and enhanced cisplatin-induced DNA damage signaling. In a matched PBMC-humanized subcutaneous CDX model (NOD/SCID), Ebselen plus cisplatin achieved stronger tumor suppression than cisplatin alone, with reduced proliferation, increased γH2AX and elevated Apoptosis. Single-cell analyses indicated that combination therapy reshaped the tumor microenvironment by shifting cellular composition and strengthening immune-cell communication, which was supported by CellChat/NicheNet and further validated by spatial transcriptomics showing altered spatial cytokine programs. Mechanistically, integrative screening identified SQSTM1 as a key regulator. Co-IP and linkage-specific IP-WB demonstrated SQSTM1 interacts with RAD51 and promotes RAD51 K48-linked polyubiquitination. Ebselen increased RAD51 protein stability in CHX-chase assays, an effect reversed by SQSTM1 reconstitution; MG132, but not chloroquine, restored RAD51 levels, indicating proteasome-dependent degradation. Functionally, SQSTM1 reconstitution attenuated Ebselen effects, while RAD51 reconstitution rescued related phenotypes. Overall, Ebselen reverses cisplatin resistance by inhibiting SQSTM1-mediated RAD51 proteasomal turnover, thereby amplifying DNA damage and remodeling antitumor immunity.