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<p>Therapeutic resistance to cytarabine (Ara-C), a cornerstone of acute myeloid leukemia (AML) therapy, remains an unmet clinical need. Here, we identify ACSF2 as a key metabolic determinant of Ara-C resistance. ACSF2 inhibition suppresses Ara-C-resistant AML cell proliferation, restores Ara-C sensitivity in vitro and in vivo. Mechanistically, ACSF2 inhibition impairs cholesterol esterification. Therefore, the increased cholesterol accumulation on mitochondrial membranes results in mitochondrial dysfunction, elevated mitochondrial reactive oxygen species (ROS), and suppression of pro-survival ERK signaling. Furthermore, we first established SREBF1 as a direct transcriptional activator of ACSF2 in this context. Notably, the SREBF1 inhibitor fatostatin synergizes with Ara-C against resistant AML with downregulation of ACSF2. These findings define a crucial role of ACSF2 in Ara-C resistance and highlight the SREBF1-ACSF2 axis as a promising therapeutic target for relapsed/refractory AML.</p><p></p>

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Targeting ACSF2 overcomes Ara-C resistance in acute myeloid leukemia via the cholesterol metabolism-ERK signaling axis

  • 期刊论文

  • 发表日期：

    2026年7月31日

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  • Chenxi Liao,
  • Jin Wen,
  • Xiao Ma,
  • Nan Wang,
  • Ying Chen,
  • Lei Li,
  • Lingbo Liu,
  • Danyue Peng

摘要

Therapeutic resistance to cytarabine (Ara-C), a cornerstone of acute myeloid leukemia (AML) therapy, remains an unmet clinical need. Here, we identify ACSF2 as a key metabolic determinant of Ara-C resistance. ACSF2 inhibition suppresses Ara-C-resistant AML cell proliferation, restores Ara-C sensitivity in vitro and in vivo. Mechanistically, ACSF2 inhibition impairs cholesterol esterification. Therefore, the increased cholesterol accumulation on mitochondrial membranes results in mitochondrial dysfunction, elevated mitochondrial reactive oxygen species (ROS), and suppression of pro-survival ERK signaling. Furthermore, we first established SREBF1 as a direct transcriptional activator of ACSF2 in this context. Notably, the SREBF1 inhibitor fatostatin synergizes with Ara-C against resistant AML with downregulation of ACSF2. These findings define a crucial role of ACSF2 in Ara-C resistance and highlight the SREBF1-ACSF2 axis as a promising therapeutic target for relapsed/refractory AML.