Photo Credit: Dr._Microbe

The following is a summary of “Disruption of the sorcin‒PAX5 protein‒protein interaction induces ferroptosis by promoting the FBXL12-mediated ubiquitination of ALDH1A1 in pancreatic cancer,” published in the March 2025 issue of Journal of Hematology & Oncology by Ding et al. 

Pancreatic cancer is highly malignant with limited treatment options. Ferroptosis induction offers a potential strategy for resistant cancers. 

Researchers conducted a retrospective study to investigate sorcin’s role in pancreatic cancer and its potential as a druggable target for ferroptosis induction.  

They assessed sorcin expression using TCGA, Gene Expression Omnibus (GEO), and immunohistochemical staining data. Ferroptosis function was investigated through proteomics, co-IP, Ch-IP, and luciferase assays. Natural product screening identified ferroptosis inducers interacting with sorcin. 

The results showed that sorcin expression correlated with survival and tumor stages in pancreatic cancer. Sorcin inhibited ferroptosis through its noncalcium binding function by interacting with PAX5, preventing its nuclear translocation, decreasing FBXL12 expression, and reducing ALDH1A1 ubiquitination. Celastrol disrupted sorcin-PAX5 interaction by binding to Cys194, promoting PAX5 nuclear translocation, increasing FBXL12 expression, enhancing ALDH1A1 ubiquitination, and inducing ferroptosis in pancreatic cancer cells. 

Investigators revealed sorcin as a druggable target for ferroptosis, identified celastrol as a ferroptosis inducer, and showed that disrupting the sorcin-PAX5 interaction was a potential therapeutic strategy for pancreatic cancer. 

Source: jhoonline.biomedcentral.com/articles/10.1186/s13045-025-01680-8