The ALDH2-PKC delta-SHMT2 axis regulates cellular metabolic plasticity to promote leukemia stem cells self-renewal and evasion of chemotherapy in AML.

Leukemia stem cells (LSCs) exhibit unique characteristics distinct from those of leukemia cells and are insensitive to conventional chemotherapeutics; thus, these cells ultimately contribute to treatment failure and relapse in acute myeloid leukemia (AML) patients. A critical challenge remains as strategies are needed to precisely target the diverse molecular drivers of leukemia stem cells (LSCs), particularly in the context of their protective microenvironment, to achieve optimal therapeutic outcomes. In this study, we investigated the role of aldehyde dehydrogenase 2 (ALDH2) in chemotherapy resistance in patients with relapsed/refractory AML and demonstrated that elevated ALDH2 expression in LSCs is closely associated with AML relapse and treatment resistance. Mechanistically, ALDH2 sustains mitochondrial homeostasis in LSCs by increasing the expression of protein kinase C delta (PKC delta) and serine hydroxymethyltransferase 2 (SHMT2), revealing a previously unidentified mechanism of metabolic reprogramming that facilitates LSC adaptation to chemotherapy-induced stress. The ALDH2‒PKC delta-SHMT2 axis plays a pivotal role in conferring resistance to chemotherapy in LSCs. Notably, rhoifolin, a compound designed to inhibit the specific binding site of ALDH2-PKC delta, significantly increased chemosensitivity. It could target LSCs within the bone marrow microenvironment, work synergistically with conventional chemotherapy drugs, and exhibit no toxicity toward normal cells. These findings underscore the therapeutic potential of targeting the ALDH2‒PKC delta axis as a novel and effective strategy for the treatment of AML and the eradication of minimal residual disease.