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

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.