HDAC11 Inhibition as a Potential Therapeutic Strategy for AML: Target Identification, Lead Discovery, Antitumor Potency, and Mechanism Investigation.

Herein, we identified that HDAC11 is involved in the pathogenesis of AML and is a potential therapeutic target for AML. Considering the scarcity of HDAC11 inhibitors, structurally novel HDAC11 inhibitors were developed, identifying A9 as the most potent one, which phenocopied the apoptosis induction, cell cycle arrest, and differentiation promotion effects of HDAC11 knockdown in AML cells. Moreover, A9 not only promoted iron uptake by upregulating TF and TFRC but also promoted iron release by upregulating HMOX1, which cooperatively led to iron homeostasis disruption and the consequent ferroptosis in AML cells. Mechanism investigation indicated that A9-induced HMOX1 upregulation was due to the activation of the p62-Keap1-Nrf2 pathway. Notably, the combination of A9 with chemotherapy drugs synergistically reduced AML cell viability in vitro. The robust in vivo anti-AML efficacy of A9, alone and combined with cytarabine, was also validated. Collectively, our study revealed pharmacological inhibition of HDAC11 as a potential therapeutic strategy for AML.