Leukemia stem cells (LSCs) are a rare subpopulation of abnormal hematopoietic stem cells (HSCs) that propagates leukemia and are responsible for the high frequency of relapse in therapies. Detailed insights into LSCs’ survival will facilitate the identification of targets for therapeutic approaches. Here, we develop an inhibitor, LYZ-81, which targets ORP4L with high affinity and specificity and selectively eradicates LCSs in vitro and in vivo. ORP4L is expressed in LSCs but not in normal HSCs and is essential for LSC bioenergetics and survival. It extracts PIP₂ from the plasma membrane and presents it to PLCβ3, enabling IP₃ generation and subsequent Ca²⁺-dependent bioenergetics. LYZ-81 binds ORP4L competitively with PIP₂ and blocks PIP₂ hydrolysis, resulting in defective Ca²⁺ signaling. The results provide evidence that LSCs can be eradicated through the inhibition of ORP4L by LYZ-81, which may serve as a starting point of drug development for the elimination of LSCs to eventually cure leukemia.

白血病干细胞（LSC）是异常的造血干细胞（HSC）的罕见亚群，其会扩散白血病并导致治疗中的高复发率。对LSC生存的详细了解将有助于确定治疗方法的靶标。在这里，我们开发了一种抑制剂LYZ-81，它以高亲和力和特异性靶向ORP4L，并在体内和体外选择性根除LCS 。ORP4L在LSC中表达，但在正常HSC中不表达，对于LSC生物能和生存至关重要。它从质膜中提取PIP ₂并将其呈现给PLCβ3，从而生成IP ₃和随后的Ca ²⁺依赖的生物能学。LYZ-81与PIP ₂竞争性结合ORP4L，并阻断PIP ₂水解，导致有缺陷的Ca ²⁺信号传导。结果提供了证据，表明可以通过LYZ-81抑制ORP4L消除LSC，这可能是消除LSC最终治愈白血病的药物开发起点。