USP8-EIF2S1 signaling enhances CML cell survival under TKI-induced stress.

CML is primarily driven by the oncogenic BCR-ABL fusion kinase; however, tyrosine kinase inhibitor (TKI) resistance remains a significant clinical challenge. A study by Zang et al. identified USP8 as a critical mediator of this resistance. USP8, a deubiquitinase, stabilizes the stress-response regulator EIF2S1 (eIF2α) by removing K48-linked ubiquitin chains. This stabilization sustains PERK-EIF2S1-mediated unfolded protein response (UPR) signaling. The UPR suppresses general protein translation while promoting the expression of adaptive stress-response genes, allowing CML cells to survive TKI-induced stress. Consequently, targeting the USP8-EIF2S1 axis is proposed as a key therapeutic strategy to overcome resistance and enhance patient outcomes.