BAP1（BRCA1 相关蛋白 1）通过 H2A 单泛素化的去泛素化和随后的基因转录调控，充当新型肿瘤抑制因子。细胞凋亡或铁死亡等受调控的细胞死亡被认为是介导肿瘤抑制的重要机制。之前的报告，包括我们的报告，已经证明 BAP1 可以促进细胞凋亡和铁死亡，从而抑制肿瘤的发展。 BAP1 是否调节其他类型的细胞死亡仍不清楚。二硫下垂症是最近发现的一种新型细胞死亡模式，其特征是细胞内二硫键（例如胱氨酸）的异常积累和 NADPH 的消耗。在本研究中，我们首先证明BAP1可以显着保护葡萄糖饥饿引起的二硫键下垂，并通过各种细胞死亡抑制剂和细胞骨架蛋白中二硫键的积累得到验证。已知 BAP1 会抑制 SLC7A11 的表达。我们发现，当过度表达 SLC7A11 或添加额外的胱氨酸时，BAP1 对二硫下垂的保护作用会被抵消。相反，当 SLC7A11 介导的胱氨酸摄取被 SLC7A11 敲除或erastin 治疗抑制时，BAP1 介导的二硫下垂抑制在很大程度上被消除。此外，高 BAP1 表达表明 NADP /NADPH 水平较低，这可能赋予对二硫下垂病的抵抗力。与这些观察结果一致，KIRC 患者中 BAP1 的表达水平也与 NADPH 相关基因呈正相关，尽管介导 NADPH 调节的潜在机制仍有待进一步研究。总之，我们的结果揭示了 BAP1 在调节二硫下垂中的作用，并为理解二硫下垂在肿瘤发展中的理解提供了新的见解。© 2024。作者。

BAP1, BRCA1-Associated Protein 1, serves as a novel tumor suppressor through the deubiquitination of monoubiquitination of H2A and subsequent gene transcriptional regulation. Regulated cell death like apoptosis or ferroptosis is considered an essential mechanism mediating tumor suppression. Previous reports, including ours, have demonstrated that BAP1 could promote apoptosis and ferroptosis to inhibit tumor development. Whether BAP1 regulated additional types of cell death remains unclear. Disulfidptosis is a recently identified novel cell death mode characterized by aberrant accumulation of intracellular disulfide (e.g., cystine) and depletion of NADPH. In this study, we first demonstrated that BAP1 could significantly protect disulfidptosis induced by glucose starvation, which is validated by various cell death inhibitors and the accumulation of disulfide bonds in the cytoskeleton proteins. BAP1 is known to inhibit SLC7A11 expression. We found that the protective effect of BAP1 against disulfidptosis was counteracted when overexpressing SLC7A11 or adding additional cystine. Conversely, BAP1-mediated suppression of disulfidptosis was largely abrogated when SLC7A11-mediated cystine uptake was inhibited by the knockout of SLC7A11 or erastin treatment. Besides, high BAP1 expression showed lower NADP+/NADPH levels, which might confer resistance to disulfidptosis. Consistent with these observations, the expression level of BAP1 was also positively correlated with NADPH-related genes in KIRC patients, though the underlying mechanism mediating NADPH regulation remains further investigation. In summary, our results revealed the role of BAP1 in the regulation disulfidptosis and provided new insights into the understanding of disulfidptosis in tumor development.© 2024. The Author(s).