2. Academic Validation
  3. Hypoxia-activated cystathionine β-synthase/H2S signaling drives drug resistance in acute myeloid leukemia through CD36-mediated fatty acid metabolism

Hypoxia-activated cystathionine β-synthase/H2S signaling drives drug resistance in acute myeloid leukemia through CD36-mediated fatty acid metabolism

  • J Leukoc Biol. 2025 Jun 4;117(6):qiaf065. doi: 10.1093/jleuko/qiaf065.
Qianpeng Li 1,  Qin Li 2,  Haifeng Han 3,  Maowen Liu 4,  Nannan Lyu 5,  Zhiyuan Qiu 1,  Rui Zhang 6,  Xiaofeng Li 7,  Xuehong Ran 1
Affiliations

Affiliations

  • 1 Department of Hematology, Weifang People's Hospital, Shandong Second Medical University, No. 151 Yuhe Road, Guangwen Street, Kuiwen District, Weifang, Shandong Province 261000, P.R. China.
  • 2 Xing'an Street Health Center, No. 197 Xing'an Road, Anqiu, Shandong Province 262100, P.R. China.
  • 3 Department of Blood Transfusion, Weifang People's Hospital, Shandong Second Medical University, No. 151 Yuhe Road, Guangwen Street, Kuiwen District, Weifang, Shandong Province 261000, P.R. China.
  • 4 Department of Imaging, Weifang People's Hospital, Shandong Second Medical University, No. 151 Yuhe Road, Guangwen Street, Kuiwen District, Weifang, Shandong Province 261000, P.R. China.
  • 5 Department of Hematology, Affiliated Hospital of Shandong Second Medical University, School of Clinical Medicine, Shandong Second Medical University, No. 2428 Yuhe Road, Kuiwen District, Weifang, Shandong Province 261000, P.R. China.
  • 6 Department of Cardiology, Weifang People's Hospital, Shandong Second Medical University, No. 151 Yuhe Road, Guangwen Street, Kuiwen District, Weifang, Shandong Province 261000, P.R. China.
  • 7 Department of Endocrinology, Anqiu Municipal Hospital, No. 380, Yong'an Road, Anqiu, Shandong Province 262100, P.R. China.
PMID: 40376852 DOI: 10.1093/jleuko/qiaf065
Abstract

Hypoxia-associated hydrogen sulfide (H2S) accumulation promotes chemotherapy resistance in solid tumor cells. This study delved into the mechanism by which cystathionine β-synthase (CBS)/H2S signaling is involved in the development of acute myeloid leukemia (AML) resistance to cytarabine (ara-C) under hypoxic conditions. The levels of CBS and H2S in AML cells and ara-C-resistant AML cells were evaluated. Subsequently, the expression of CBS and H2S under normoxic and hypoxic conditions in ara-C-resistant AML cells was further scrutinized. sh-CBS or sh-thrombospondin 1 (THBS1) was transfected into ara-C-resistant AML cells, which were then exposed to 1% oxygen and/or ara-C. The cell viability, Apoptosis, and lipid metabolism level were evaluated by the cell counting kit-8, flow cytometry, kit, and qPCR. Simultaneously, the methylation of THBS1 was detected via methylation-specific PCR analysis. The expression of CBS and H2S is elevated in ara-C-resistant AML cells, rising proportionally with diminishing oxygen concentration. In ara-C-resistant AML cells, hypoxia stimulated cell viability, suppressed Apoptosis, augmented total Cholesterol and triacylglycerol levels, upregulated the levels of CD36 and carnitine palmitoyltransferase-1α, as well as downregulated short-chain acyl-CoA dehydrogenase and Peroxisome Proliferator-activated Receptor α levels, while these effects of hypoxia were all reversed by sh-CBS. sh-CBS notably decreases the hypermethylation level of THBS1 in ara-C-resistant AML cells. sh-THBS1 reversed the regulatory effect of sh-CBS on lipid metabolism, cell viability, and Apoptosis in ara-C-resistant AML cells. Conversely, sh-CD36 effectively overrode the reversal impact of sh-THBS1. Activation of CBS/H2S signaling in a hypoxic environment participates in the ara-C resistance of AML cells by facilitating CD36-mediated fatty acid metabolism through the mediation of THBS1 methylation.

Keywords

acute myeloid leukemia; cytarabine resistance; hydrogen sulfide; hypoxia; thrombospondin 1.

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