Induction of ferroptosis by SIRT1 knockdown alleviates cytarabine resistance in acute myeloid leukemia by activating the HMGB1/ACSL4 pathway

Kong,Qian; Liang,Qixiang; Tan,Yinli; Luo,Xiangqin; Ling,Yesheng; Li,Xiaofeng; Cai,Yun; Chen,Huiqin

doi:10.3892/ijo.2024.5708

Induction of ferroptosis by SIRT1 knockdown alleviates cytarabine resistance in acute myeloid leukemia by activating the HMGB1/ACSL4 pathway

Authors:
- Qian Kong
- Qixiang Liang
- Yinli Tan
- Xiangqin Luo
- Yesheng Ling
- Xiaofeng Li
- Yun Cai
- Huiqin Chen
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Affiliations: Department of Pediatrics, The Third Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510000, P.R. China, Department of Stomatology, The Third Affiliated Hospital of Sun Yat‑Sen University, Guangzhou, Guangdong 510000, P.R. China
Published online on: November 19, 2024 https://doi.org/10.3892/ijo.2024.5708
Article Number: 2
Copyright: © Kong et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Resistance to cytarabine is a major obstacle to the successful treatment of acute myeloid leukemia (AML). The present study aimed to explore the mechanism by which sirtuin 1 (SIRT1) reverses the cytarabine resistance of leukemia cells. Cell viability was investigated using the EdU proliferation assay. The expression levels of molecules were determined by reverse transcription‑quantitative PCR, western blotting, and immunofluorescence staining. Flow cytometry was used to detect reactive oxygen species and apoptosis levels, The levels of superoxide dismutase, glutathione and malondialdehyde were examined by ELISA. Mitochondrial damage was investigated by transmission electron microscopy. Furthermore, tumor growth was evaluated in a xenograft model. The results revealed that SIRT1 expression was significantly upregulated in drug‑resistant leukemia cells. By contrast, knockdown of SIRT1 reversed cytarabine resistance in HL60 cells by promoting ferroptosis. Mechanistically, SIRT1 could regulate the translocation of HMGB1 from the nucleus to the cytoplasm in cytarabine‑resistant HL60 (HL60/C) cells. Furthermore, knockdown of HMGB1 inhibited the expression of ACSL4. In addition, knockdown of SIRT1 expression could inhibit the growth of HL60/C cells in vivo and reverse cytarabine resistance. In conclusion, the present results demonstrated that SIRT1 inhibition could be a promising strategy to overcome cytarabine resistance in AML.

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