Publication

Abstract : 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.