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LAPTM5 is mainly expressed in hematopoietic and immune cells, and has been associated with the progression of multiple cancers; however, its role in AML drug resistance remains uncharacterized. Here, we reanalyzed publicly available single-cell RNA sequencing (scRNA-seq) data from AML patients and found distinct gene expression profiles between AraC-resistant AML cells and untreated controls. Differentially expressed genes were significantly enriched in lysosome-related pathways, with LAPTM5 being highly expressed in drug-resistant cells, suggesting that it may be a key mediator of AraC resistance in AML. Mechanistically, AraC-resistant cells exhibited enhanced autophagic flux supported by LAPTM5-mediated upregulation of LAMP1 and LAMP2. Conversely, LAPTM5 knockdown impaired autophagolysosome formation by disrupting lysosomal biogenesis, thereby sensitizing resistant cells to AraC. These findings indicate that targeting LAPTM5 could enhance AraC sensitivity in AML by modulating autophagy. In vivo experiments further confirmed that the depletion of LAPTM5 inhibited tumor growth and synergistically suppressed AML progression with AraC. Collectively, our study identifies LAPTM5 as a critical regulator of AraC resistance via autophagy modulation, highlighting its potential as a therapeutic target for AML.<\/jats:p>","DOI":"10.1038\/s41419-026-08654-9","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T12:40:09Z","timestamp":1774874409000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Targeting LAPTM5 enhances AML sensitivity to cytarabine through autophagy inhibition"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7582-4544","authenticated-orcid":false,"given":"Yuqing","family":"Zeng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6224-3484","authenticated-orcid":false,"given":"Chao","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0954-5600","authenticated-orcid":false,"given":"Hongbo","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8260-9244","authenticated-orcid":false,"given":"Fang","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,30]]},"reference":[{"key":"8654_CR1","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1186\/s13045-023-01424-6","volume":"16","author":"RS Bhansali","year":"2023","unstructured":"Bhansali RS, Pratz KW, Lai C. 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