Work

BMAL1-depletion remodels ceramide metabolism to regulate ferroptosis and sorafenib chemosensitivity in acute myeloid leukemia

Year: 2025

Type: article

Abstract: Acute myeloid leukemia (AML) is a hematologic malignancy with a poor prognosis. We discovered that BMAL1 is a ferroptosis suppressor. Furthermore, it was also found to be overexpressed in AML patients, affecting the cell cycle and promoting tumor cell growth and progression. In this study, we further validated the association of BMAL1 with the progression and survival outcomes of AML. Lipidomic revealed that the levels of ceramide increased in AML cells following the depletion of BMAL1. Ceramide facilitated ferroptosis in AML cells. ASAH2 played a key role in this process. BMAL1 could not directly regulate ASAH2 but instead through IKZF2. Elevated levels of ceramide promoted the degradation of the ferroptosis protection molecule GPX4, ultimately promoting ferroptosis. Furthermore, ceramide treatment has been demonstrated to enhance the responsiveness of AML cells to sorafenib. In summary, this study elucidates that BMAL1 depletion remodels ceramide metabolism to regulate the sensitivity of AML cells to ferroptosis and targeted drug sorafenib.

Source: iScience

DOI: 10.1016/j.isci.2025.112054