Functional role of deubiquitinating enzyme USP39 in inhibiting pyroptosis in human acute myeloid leukemia.

Acute myeloid leukemia (AML) exhibits a five-year overall survival rate below 30%, with its substantial genetic heterogeneity/clonal evolution complicating therapeutic strategies. Pyroptosis, inflammatory programmed cell death via Gasdermins holds therapeutic potential for AML. Deubiquitinase USP39 highly expressed in leukemia and linked to poor prognosis regulates pyroptosis in AML cells via an unclear mechanism. This study aims to explore this mechanism. The TCGA, GTEx, and GSE138702 datasets were applied for analysis of USP family genes differentially expressed. The biological behavior changes of MOLM13 and THP-1 cells after USP39 knockdown were evaluated by MTT, cell cycle, and apoptosis assays. The key genes regulated by USP39 in AML were identified by RNA-seq. Changes in pyroptosis-related pathways indicators after USP39 knockdown were analyzed by ROS detection, ELISA and Western Blot. Adverse prognosis in AML patients exhibited significant correlation with elevated USP39 expression. After USP39 knockdown, cell viability decreased while the level of apoptosis of AML cells increased, with a significant increase in the proportion of G0/G1 phase cells. Mechanistically, RNA-seq identified SQSTM1 as a key target regulated by USP39. USP39 knockdown leads to elevated SQSTM1 levels and significant upregulation of key pyroptotic proteins, with secretions of inflammatory factors increased and ROS accumulated significantly. USP39 inhibits pyroptosis in AML cells by regulating the activation of NLRP3 inflammasome and cleavage of Gasdermin D. The high expression of USP39 is correlated with adverse prognosis in patients, which suggested that USP39 may be an important part of the overall understanding of AML pyroptosis pathways.