lncRNA XIST suppresses acute myeloid leukemia progression by promoting necroptosis through the miR-92a-3p/CYLD axis

Acute myeloid leukemia (AML) remains a highly lethal hematologic malignancy, with relapse and therapeutic resistance largely driven by apoptosis evasion. Necroptosis, a regulated form of non-apoptotic cell death, has emerged as a potential strategy to eliminate apoptosis-resistant cancer cells; however, its upstream regulatory mechanisms in AML remain incompletely understood. Here, we identify the long non-coding RNA XIST as a previously underappreciated regulator of necroptosis-associated signaling in AML. XIST and CYLD were consistently downregulated in AML cell lines and primary patient samples, whereas miR-92a-3p was upregulated and inversely correlated with XIST and CYLD expression. Clinically, elevated miR-92a-3p expression was associated with inferior overall survival in AML patients. Functionally, endogenous activation of XIST significantly suppressed AML cell proliferation and induced G2/M cell cycle arrest without markedly increasing apoptosis. Instead, XIST overexpression increased membrane-disrupted cell death, as shown by trypan blue and Hoechst/PI staining, and induced necroptosis-like ultrastructural changes. XIST-mediated growth inhibition was partially rescued by the necroptosis inhibitor Necrostatin-1 but not by the pan-caspase inhibitor zVAD-fmk. Moreover, XIST overexpression enhanced CYLD expression and activated necroptosis-associated RIPK1/RIPK3/MLKL signaling, including increased phosphorylation of RIPK1, RIPK3, and MLKL. Mechanistically, XIST directly interacted with miR-92a-3p and negatively regulated its expression, while miR-92a-3p directly targeted CYLD. Inhibition of miR-92a-3p increased CYLD expression and recapitulated the anti-proliferative and necroptosis-associated effects of XIST. In vivo, XIST overexpression suppressed subcutaneous AML xenograft growth and enhanced necroptosis-associated signaling. Collectively, our findings suggest that XIST restrains AML progression, at least in part, by modulating the miR-92a-3p/CYLD axis and promoting necroptosis-associated cell death, highlighting a potential regulatory mechanism for overcoming apoptosis resistance in AML.