CAPZB suppresses disulfidptosis through SQOR interaction to drive intrahepatic cholangiocarcinoma progression and therapeutic vulnerability

Background: Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy with limited therapeutic options. Disulfidptosis, a novel cell death modality triggered by disulfide stress, represents a promising therapeutic target. While CAPZB has been implicated in disulfidptosis, its role in ICC remains undefined. This study investigates whether CAPZB regulates disulfidptosis via SQOR to promote ICC progression. Methods: Transcriptomic analysis of three ICC cohorts (n=98) and single-cell RNA-seq (n=4) evaluated CAPZB expression and prognostic significance. CAPZB was genetically modulated in ICC cell lines using shRNA/overexpression constructs. Disulfidptosis was induced by glucose deprivation and assessed via cell viability, F-actin staining, and NADP+/NADPH/GSH/GSSG ratios. Protein interactions were identified by IP-MS and validated by co-immunoprecipitation. AKT/NICD mouse models evaluated in vivo tumor progression. Patient-derived organoids were treated with GLUT1 inhibitor BAY-876. Results: CAPZB was significantly overexpressed in ICC tissues and correlated with poor overall survival (p<0.01). Single-cell analysis revealed elevated CAPZB in malignant cholangiocytes. CAPZB knockdown suppressed proliferation, migration, and invasion, while overexpression enhanced malignant phenotypes. IP-MS identified SQOR as a CAPZB-interacting protein, with strong expression correlation (p<0.001). CAPZB knockdown promoted disulfidptosis under glucose deprivation, increasing cell death (p<0.001), F-actin contraction, and NADP+/NADPH ratio. SQOR overexpression partially rescued these effects. In vivo, CAPZB knockdown reduced tumor burden (p<0.01). Patient-derived organoids showed BAY-876 sensitivity (IC₅₀=0.315 μM). Combination therapy with CAPZB knockdown and BAY-876 demonstrated synergistic anti-tumor efficacy (p<0.001). Conclusions: CAPZB is a disulfidptosis-related oncogene that drives ICC progression by interacting with SQOR to maintain redox homeostasis and suppress disulfidptosis. Targeting CAPZB alone or with GLUT1 inhibitors induces synthetic lethality via disulfidptosis, offering a promising therapeutic strategy. Clinical Significance: This study identifies the CAPZB-SQOR axis as a novel disulfidptosis regulator in ICC and demonstrates synergistic anti-tumor effects of dual targeting CAPZB and glucose metabolism, providing a translational framework for disulfidptosis-based therapies.