Targeting HSPA8 to repress GPX4 and induce ferroptosis in BCR-ABL positive leukemia

BCR-ABL positive (BCR-ABL+) leukemia is driven by constitutive activation of tyrosine kinase activity, with tyrosine kinase inhibitors (TKIs) serving as the standard treatment. However, resistance to TKIs remains a significant clinical challenge. In this study, we demonstrate that HSPA8 is highly expressed in BCR-ABL+ ​leukemia cells, and elevated HSPA8 expression correlates with poor prognosis in BCR-ABL+ ​B-acute lymphoblastic leukemia (B-ALL). Inhibition of HSPA8 using Apoptozole (Az) or VER15508 (VER) reduced the viability of BCR-ABL+ ​leukemia cells, induced cell death, and suppressed colony formation. Through proteomic analysis, we identified GPX4, a key regulator of ferroptosis, as a major target of HSPA8 inhibition. Notably, co-treatment with HSPA8 inhibitors and GPX4 inhibitors (RSL3), or TKIs, synergistically downregulated GPX4 expression and induced ferroptosis in BCR-ABL+ ​leukemia cells, including those resistant to TKIs. In vivo, combination therapy with Az and RSL3 significantly prolonged survival in a BCR-ABL+ ​leukemia mouse model. Overall, our findings provide compelling evidence that targeting HSPA8, in combination with GPX4 inhibition or TKIs, can effectively induce ferroptosis, overcome drug resistance, and offer a novel therapeutic strategy for these malignancies.