FTO promotes multiple myeloma progression by posttranscriptional activation of HSF1 in an m⁶A-YTHDF2-dependent manner

N⁶-methyladenosine (m⁶A), as the most pervasive internal modification of eukaryotic mRNA, plays a crucial role in various cancers, but its role in multiple myeloma (MM) pathogenesis has not yet been investigated. In this study, we revealed significantly decreased m⁶A methylation in plasma cells (PCs) from MM patients and showed that the abnormal m⁶A level resulted mainly from upregulation of the demethylase fat mass and obesity-associated protein (FTO). Gain- and loss-of-function studies demonstrated that FTO plays a tumor-promoting and pro-metastatic role in MM. Combined m⁶A and RNA sequencing (RNA-seq) and subsequent validation and functional studies identified heat shock factor 1 (HSF1) as a functional target of FTO-mediated m⁶A modification. FTO significantly promotes MM cell proliferation, migration, and invasion by targeting HSF1/HSPs in a YTHDF2-dependent manner. FTO inhibition, especially when combined with bortezomib (BTZ) treatment, synergistically inhibited myeloma bone tumor formation and extramedullary spread in NOD-Prkdc^em26Cd52il2rg^em26Cd22/Nju (NCG) mice. We demonstrated the functional importance of m⁶A demethylase FTO in MM progression, especially in promoting extramedullary myeloma (EMM) formation, and proposed the FTO-HSF1/HSP axis as a potential novel therapeutic target in MM.