{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T18:37:30Z","timestamp":1790620650903,"version":"4.1.0"},"reference-count":32,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T00:00:00Z","timestamp":1747958400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Xinjiang Key Laboratory of Active Components of Natural Medicine and Drug Release Technology","award":["XJDX1713"],"award-info":[{"award-number":["XJDX1713"]}]},{"name":"Xinjiang Key Laboratory of Active Components of Natural Medicine and Drug Release Technology","award":["XYD2024GR07"],"award-info":[{"award-number":["XYD2024GR07"]}]},{"name":"National Youth Talent Training Program of Xinjiang Medical University","award":["XJDX1713"],"award-info":[{"award-number":["XJDX1713"]}]},{"name":"National Youth Talent Training Program of Xinjiang Medical University","award":["XYD2024GR07"],"award-info":[{"award-number":["XYD2024GR07"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Leukemia is a malignant tumor of the hematopoietic system. Approximately 15% of adult leukemias are chronic myeloid leukemias (CMLs), and this incidence increases annually. The BCR-ABL oncoprotein drives the initiation, promotion, and progression of CML. Although tyrosine kinase inhibitors (TKIs) are first-line therapies for CML, BCR-ABL-mediated drug resistance limits their clinical efficacy and patient prognosis. Perillaldehyde (PAE), a monoterpene and primary volatile oil from perilla, is a promising small-molecule candidate for degrading BCR-ABL and has potential medical applications. The molecular mechanism showed that PAE regulated the expression of autophagy- and apoptosis-related proteins in K562 cells. Confocal laser observation showed that PAE damaged the mitochondrial membrane potential and induced ROS generation. Further evaluations indicated that PAE targeted HSP70 and inactivated the phosphorylation of BCR-ABL, thereby inhibiting its downstream proteins. This study may produce a lead compound for CML therapy as PAE may be an effective treatment for further exploration.<\/jats:p>","DOI":"10.3390\/molecules30112294","type":"journal-article","created":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T09:58:09Z","timestamp":1747994289000},"page":"2294","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Unlocking the Potential of Perillaldehyde: A Novel Mechanism for Chronic Myeloid Leukemia by Targeting HSP70"],"prefix":"10.3390","volume":"30","author":[{"given":"Miaomiao","family":"Zhang","sequence":"first","affiliation":[{"name":"School of Pharmacy, Xinjiang Medical University, Urumchi 830017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinfeng","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Xinjiang Medical University, Urumchi 830017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongsong","family":"Jiang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Xinjiang Medical University, Urumchi 830017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Xinjiang Medical University, Urumchi 830017, China"},{"name":"Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiyi","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Xinjiang Medical University, Urumchi 830017, China"},{"name":"Xinjiang Key Laboratory of Natural Medicines Active Components and Drug Release Technology, Urumchi 830017, China"},{"name":"Xinjiang Key Laboratory of Biopharmaceuticals and Medical Devices, Urumchi 830017, China"},{"name":"Engineering Research Center of Xinjiang and Central Asian Medicine Resources, Ministry of Education, Urumchi 830017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1002\/ajh.26642","article-title":"Chronic myeloid leukemia: 2022 update on diagnosis, therapy, and monitoring","volume":"97","author":"Jabbour","year":"2022","journal-title":"Am. J. Hematol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Al-Rawashde, F.A., Al-Sanabra, O.M., Alqaraleh, M., Jaradat, A.Q., Al-Wajeeh, A.S., Johan, M.F., Wan Taib, W.R., Ismail, I., and Al-Jamal, H.A.N. (2023). Thymoquinone Enhances Apoptosis of K562 Chronic Myeloid Leukemia Cells through Hypomethylation of SHP-1 and Inhibition of JAK\/STAT Signaling Pathway. Pharmaceuticals, 16.","DOI":"10.3390\/ph16060884"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1002\/ajh.25792","article-title":"Chronic myeloid leukemia: 2020 update on diagnosis, therapy and monitoring","volume":"95","author":"Jabbour","year":"2020","journal-title":"Am. J. Hematol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2213","DOI":"10.1080\/10428194.2022.2068000","article-title":"Long-term outcomes of patients with Chronic Myeloid Leukemia who commenced treatment with imatinib: A 20-year single-centre experience","volume":"63","author":"Szczepanek","year":"2022","journal-title":"Leuk. Lymphoma"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Alves, R., Gon\u00e7alves, A.C., Rutella, S., Almeida, A.M., De Las Rivas, J., Trougakos, I.P., and Sarmento Ribeiro, A.B. (2021). Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia-From Molecular Mechanisms to Clinical Relevance. Cancers, 13.","DOI":"10.3390\/cancers13194820"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.1016\/j.drudis.2019.05.007","article-title":"Current outlook on drug resistance in chronic myeloid leukemia (CML) and potential therapeutic options","volume":"24","author":"Jiang","year":"2019","journal-title":"Drug Discov. Today"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1007\/978-981-15-4272-5_53","article-title":"Natural Product Regulates Autophagy in Cancer","volume":"1207","author":"Xiaokaiti","year":"2020","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1007\/s11418-019-01306-7","article-title":"Determination of perillaldehyde in perilla herbs using relative molar sensitivity to single-reference diphenyl sulfone","volume":"73","author":"Masumoto","year":"2019","journal-title":"J. Nat. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.3389\/fmicb.2018.01102","article-title":"Perillaldehyde Controls Postharvest Black Rot Caused by Ceratocystis fimbriata in Sweet Potatoes","volume":"9","author":"Zhang","year":"2018","journal-title":"Front. Microbiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"111641","DOI":"10.1016\/j.intimp.2024.111641","article-title":"Perillaldehyde ameliorates lipopolysaccharide-induced acute lung injury via suppressing the cGAS\/STING signaling pathway","volume":"130","author":"Wei","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2710","DOI":"10.1080\/21655979.2021.2001237","article-title":"Perillaldehyde inhibits bone metastasis and receptor activator of nuclear factor-\u03baB ligand (RANKL) signaling-induced osteoclastogenesis in prostate cancer cell lines","volume":"13","author":"Lin","year":"2022","journal-title":"Bioengineered"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"6328","DOI":"10.1080\/10408398.2021.1900060","article-title":"Recent development in biological activities and safety concerns of perillaldehyde from perilla plants: A review","volume":"62","author":"Erhunmwunsee","year":"2022","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1080\/02713683.2022.2093382","article-title":"Perillaldehyde Protects Against Aspergillus fumigatus Keratitis by Reducing Fungal Load and Inhibiting Inflammatory Cytokines and LOX-1","volume":"47","author":"He","year":"2022","journal-title":"Curr. Eye Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"114201","DOI":"10.1016\/j.bcp.2020.114201","article-title":"Perillaldehyde: A promising antifungal agent to treat oropharyngeal candidiasis","volume":"180","author":"Chen","year":"2020","journal-title":"Biochem. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3587","DOI":"10.1021\/jf7037696","article-title":"Increasing antioxidant activity and reducing decay of blueberries by essential oils","volume":"56","author":"Wang","year":"2008","journal-title":"J. Agric. Food Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"113662","DOI":"10.1016\/j.biopha.2022.113662","article-title":"Perillaldehyde is a new ferroptosis inducer with a relevant clinical potential for acute myeloid leukemia therapy","volume":"154","author":"Catanzaro","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Zhao, K., Zhou, G., Liu, Y., Zhang, J., Chen, Y., Liu, L., and Zhang, G. (2023). HSP70 Family in Cancer: Signaling Mechanisms and Therapeutic Advances. Biomolecules, 13.","DOI":"10.3390\/biom13040601"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Werner, C., Stangl, S., Salvermoser, L., Schwab, M., Shevtsov, M., Xanthopoulos, A., Wang, F., Dezfouli, A.B., Th\u00f6lke, D., and Ostheimer, C. (2021). Hsp70 in Liquid Biopsies-A Tumor-Specific Biomarker for Detection and Response Monitoring in Cancer. Cancers, 13.","DOI":"10.3390\/cancers13153706"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Singh, M.K., Han, S., Ju, S., Ranbhise, J.S., Ha, J., Yeo, S.G., Kim, S.S., and Kang, I. (2025). Hsp70: A Multifunctional Chaperone in Maintaining Proteostasis and Its Implications in Human Disease. Cells, 14.","DOI":"10.3390\/cells14070509"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3921","DOI":"10.3390\/cancers3043921","article-title":"Inducible hsp70 in the regulation of cancer cell survival: Analysis of chaperone induction, expression and activity","volume":"3","author":"Zorzi","year":"2011","journal-title":"Cancers"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1038\/s41419-020-2304-8","article-title":"Tetrahydrobenzimidazole TMQ0153 triggers apoptosis, autophagy and necroptosis crosstalk in chronic myeloid leukemia","volume":"11","author":"Song","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.semcdb.2019.05.022","article-title":"Mitochondria as playmakers of apoptosis, autophagy and senescence","volume":"98","author":"Abate","year":"2020","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1540","DOI":"10.1096\/fj.201801417R","article-title":"Tissue-specific regulation of cytochrome c by post-translational modifications: Respiration, the mitochondrial membrane potential, ROS, and apoptosis","volume":"33","author":"Kalpage","year":"2019","journal-title":"FASEB J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3477","DOI":"10.3168\/jds.2021-21259","article-title":"\u03b2-Hydroxybutyrate inhibits apoptosis in bovine neutrophils through activating ERK1\/2 and AKT signaling pathways","volume":"105","author":"Song","year":"2022","journal-title":"J. Dairy. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3959","DOI":"10.31557\/APJCP.2021.22.12.3959","article-title":"Thymoquinone Induces Downregulation of BCR-ABL\/JAK\/STAT Pathway and Apoptosis in K562 Leukemia Cells","volume":"22","author":"Ismail","year":"2021","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Al-Rawashde, F.A., Al-Wajeeh, A.S., Vishkaei, M.N., Saad, H.K.M., Johan, M.F., Taib, W.R.W., Ismail, I., and Al-Jamal, H.A.N. (2022). Thymoquinone Inhibits JAK\/STAT and PI3K\/Akt\/ mTOR Signaling Pathways in MV4-11 and K562 Myeloid Leukemia Cells. Pharmaceuticals, 15.","DOI":"10.3390\/ph15091123"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1507658","DOI":"10.3389\/fonc.2024.1507658","article-title":"Newly emerged ROS1 rearrangement in a patient with lung adenocarcinoma following resistance to immune checkpoint inhibitors: A case report","volume":"14","author":"Wang","year":"2024","journal-title":"Front. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"S3","DOI":"10.1053\/j.seminoncol.2011.01.016","article-title":"Nilotinib: A novel, selective tyrosine kinase inhibitor","volume":"38","author":"Blay","year":"2011","journal-title":"Semin. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1126\/science.1099480","article-title":"Overriding imatinib resistance with a novel ABL kinase inhibitor","volume":"305","author":"Shah","year":"2004","journal-title":"Science"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2621","DOI":"10.1172\/JCI84565","article-title":"S6K1 regulates hematopoietic stem cell self-renewal and leukemia maintenance","volume":"126","author":"Ghosh","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1080\/01635581.2014.894099","article-title":"Therapeutic potential of apigenin, a plant flavonoid, for imatinib-sensitive and resistant chronic myeloid leukemia cells","volume":"66","author":"Solmaz","year":"2014","journal-title":"Nutr. Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Feriotto, G., Tagliati, F., Giriolo, R., Casciano, F., Tabolacci, C., Beninati, S., Khan, M.T.H., and Mischiati, C. (2021). Caffeic Acid Enhances the Anti-Leukemic Effect of Imatinib on Chronic Myeloid Leukemia Cells and Triggers Apoptosis in Cells Sensitive and Resistant to Imatinib. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22041644"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/11\/2294\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:39:25Z","timestamp":1760031565000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/11\/2294"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,23]]},"references-count":32,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["molecules30112294"],"URL":"https:\/\/doi.org\/10.3390\/molecules30112294","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,23]]}}}