PO.MCB02.01 · 分子与细胞生物学
CAPZB通过与SQOR相互作用抑制disulfidptosis（二硫化物死亡），驱动肝内胆管癌进展并带来治疗脆弱性
CAPZB suppresses disulfidptosis through SQOR interaction to drive intrahepatic cholangiocarcinoma progression and therapeutic vulnerability
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摘要 Abstract
中文摘要
背景：肝内胆管癌（ICC）是一种侵袭性恶性肿瘤，治疗选择有限。Disulfidptosis（二硫化物死亡）是一种由二硫化物应激触发的新型细胞死亡方式，代表了一个有前景的治疗靶点。虽然CAPZB已被认为与disulfidptosis相关，但其在ICC中的作用仍未明确。本研究探讨CAPZB是否通过SQOR调控disulfidptosis以促进ICC进展。
方法：对三个ICC队列（n=98）进行转录组分析，并对单细胞RNA-seq（n=4）评估CAPZB表达和预后意义。使用shRNA/过表达构建体在ICC细胞系中进行CAPZB的基因调控。通过葡萄糖剥夺诱导disulfidptosis，并通过细胞活力、F-actin染色和NADP+/NADPH/GSH/GSSG比值进行评估。通过IP-MS鉴定蛋白相互作用，并通过免疫共沉淀验证。使用AKT/NICD小鼠模型评估体内肿瘤进展。使用GLUT1抑制剂BAY-876处理患者来源类器官。
结果：CAPZB在ICC组织中显著过表达，并与不良总生存相关（p<0.01）。单细胞分析显示恶性胆管细胞中CAPZB升高。CAPZB敲低抑制增殖、迁移和侵袭，而过表达增强恶性表型。IP-MS鉴定出SQOR为CAPZB相互作用蛋白，二者表达强相关（p<0.001）。CAPZB敲低在葡萄糖剥夺下促进disulfidptosis，增加细胞死亡（p<0.001）、F-actin收缩和NADP+/NADPH比值。SQOR过表达部分挽救了这些效应。在体内，CAPZB敲低减少了肿瘤负荷（p<0.01）。患者来源类器官显示对BAY-876敏感（IC₅₀=0.315μM）。CAPZB敲低与BAY-876的联合治疗显示出协同抗肿瘤疗效（p<0.001）。结论：CAPZB是一种disulfidptosis相关的癌基因，通过与SQOR相互作用维持氧化还原稳态并抑制disulfidptosis，从而驱动ICC进展。单独靶向CAPZB或联合GLUT1抑制剂可通过disulfidptosis诱导合成致死，提供了一种有前景的治疗策略。
临床意义：本研究鉴定出CAPZB-SQOR轴为ICC中一种新型disulfidptosis调节因子，并证明了双重靶向CAPZB和葡萄糖代谢的协同抗肿瘤效应，为基于disulfidptosis的疗法提供了转化框架。
查看英文原文 English abstract
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.
利益披露 Disclosure
J. Yao, None..
T. Chen, None..
Z. Chen, None..
G. Chen, None..
C. Zheng, None..
Y. Wang, None.