巨自噬/自噬是一种溶酶体调节的降解过程，参与细胞应激，然后促进细胞存活或触发细胞死亡。铁死亡最初被描述为一种不依赖自噬的、铁调节的、非凋亡的细胞死亡。然而，最近的研究表明，自噬与铁死亡的敏感性呈正相关。尽管如此，这两种类型的调节性细胞死亡（RCD）相互调节的分子机制仍不清楚。在这里，我们筛选了85种去泛素化酶（DUB），发现USP13（泛素特异性肽酶13）的过表达可以显着上调NFE2L2/NRF2（NFE2类似bZIP转录因子2）蛋白水平。此外，在39例KRAS突变的肺腺癌（LUAD）中，我们发现大约76%的USP13过表达与NFE2L2过表达呈正相关。USP13与转录因子NFE2L2相互作用并催化其去泛素化。此外，USP13 耗竭通过激活 KRAS 突变细胞和肿瘤组织中的 NFE2L2-SQSTM1/p62 (sequestosome 1)-KEAP1 轴，促进体外和异种移植肿瘤小鼠模型中自噬到铁死亡的转换。因此，靶向USP13有效地将自噬转变为铁死亡，从而抑制KRAS（KRAS原癌基因，GTP酶）突变体LUAD，这表明在KRAS突变体LUAD中结合自噬和铁死亡的治疗前景。

Macroautophagy/autophagyis a lysosomal-regulated degradation process that participates incellular stress and then promotes cell survival or triggers celldeath. Ferroptosis was initially described as anautophagy-independent, iron-regulated, nonapoptotic cell death.However, recent studies have revealed that autophagy is positivelyassociated with sensitivity to ferroptosis. Nonetheless, themolecular mechanisms by which these two types of regulated cell death(RCD) modulate each other remain largely unclear. Here, we screened85 deubiquitinating enzymes (DUBs) and found that overexpression ofUSP13 (ubiquitin specific peptidase 13) could significantlyupregulate NFE2L2/NRF2 (NFE2 like bZIP transcription factor 2)protein levels. In addition, in 39 cases of KRAS-mutated lungadenocarcinoma (LUAD), we found that approximately 76% of USP13overexpression is positively correlated with NFE2L2 overexpression.USP13 interacts with and catalyzes the deubiquitination of thetranscription factor NFE2L2. Additionally, USP13 depletion promotesan autophagy-to-ferroptosis switch invitro andin xenograft tumor mouse models, through the activation of theNFE2L2-SQSTM1/p62 (sequestosome 1)-KEAP1 axis in KRAS mutant cellsand tumor tissues. Hence, targeting USP13 effectively switchedautophagy-to-ferroptosis, thereby inhibiting KRAS (KRASproto-oncogene, GTPase) mutant LUAD, suggesting the therapeuticpromise of combining autophagy and ferroptosis in the KRAS-mutantLUAD.