铁死亡是一种受氧化损伤诱导的脂质过氧化引发的调控性细胞死亡形式。然而，铁死亡的详细蛋白质翻译后修饰调控机制尚不完全清楚。在这里，我们报告了E1A结合蛋白P300（EP300）乙酰转移酶通过乙酰化热休克蛋白家族A（Hsp70）成员5（HSPA5），也被称为GRP78或BIP，促进人胰腺导管腺癌（PDAC）细胞的铁死亡，乙酰化位点为K353。乙酰化的HSPA5失去了抑制脂质过氧化和随后的铁死亡的能力。遗传或药物抑制EP300介导的在K353上的HSPA5乙酰化增加了PDAC细胞对铁死亡的抵抗力。此外，组蛋白去乙酰化酶6（HDAC6）限制了HSPA5的乙酰化和随后的铁死亡。综上所述，这些发现不仅确定了HSPA5乙酰化在铁死亡过程中的调节途径，也强调了在PDAC细胞中增加铁死亡敏感性的有前途的策略。© 2023 Springer Nature Limited.

Ferroptosis is a form of regulated cell death characterized by oxidative injury-induced lipid peroxidation. However, the detailed protein post-translational modification regulatory mechanism of ferroptosis remains largely unknown. Here, we report that E1A binding protein P300 (EP300) acetyltransferase promotes ferroptosis in human pancreatic ductal adenocarcinoma (PDAC) cells via the acetylation of heat shock protein family A (Hsp70) member 5 (HSPA5), also known as GRP78 or BIP) on the site of K353. Acetylated HSPA5 loses its ability to inhibit lipid peroxidation and subsequent ferroptotic cell death. Genetic or pharmacological inhibition of EP300-mediated HSPA5 acetylation on K353 increases PDAC cell resistance to ferroptosis. Moreover, histone deacetylase 6 (HDAC6) limits HSPA5 acetylation and subsequent ferroptosis. Collectively, these findings not only identify regulatory pathways for HSPA5 acetylation during ferroptosis, but also highlight promising strategies to increase ferroptosis sensitivity in PDAC cells.© 2023. Springer Nature Limited.