{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T17:53:58Z","timestamp":1791395638816,"version":"4.3.3"},"reference-count":75,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T00:00:00Z","timestamp":1761004800000},"content-version":"vor","delay-in-days":20,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Health Science Reports"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Myeloid cell leukemia\u20101 protein (MCL\u20101) is a major anti\u2010apoptotic member of the Bcl\u20102 family and is typically overexpressed in a broad range of malignancies, including non\u2010small\u2010cell lung cancer, multiple myeloma, acute myeloid leukemia, and various solid tumors. By sequestering pro\u2010apoptotic effectors, MCL\u20101 maintains mitochondrial stability and supports the tumor cell survival during stress, driving disease progression, therapeutic resistance, and ultimately, poor patient outcomes. In the last 10 years, the development of selective small\u2010molecule inhibitors of MCL\u20101 has opened doors to enable the targeting of this mechanism of apoptosis avoidance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>This perspective summarizes the current knowledge regarding the dual roles of MCL\u20101 in apoptosis and mitochondrial homeostasis regulation. The structural foundations for the design of MCL\u20101 inhibitors are revisited, the pharmacological profiles of the leading drugs (S63845, AZD5991, AMG 176) in advanced clinical development are summarized, and emerging strategies, such as combination therapies with inhibitors of anti\u2010apoptotic proteins such as BCL\u20102, PROTAC strategies designed to degrade MCL\u20101, and reversible\u2010binding chemotypes to maximize MCL\u20101 inhibition and minimize toxicity, are reviewed. The non\u2010apoptotic roles of MCL\u20101 in immune modulation and metabolism adaptation are also reviewed, along with the development of analytical methods to refine the patient selection process (e.g., BH3 profiling and transcriptomic signatures). The overexpression of MCL\u20101 is associated with worse patient survival in ACC, CESC, ESCA, HNSC, LGG, and UVM cancers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>MCL\u20101 is an exciting anti\u2010cancer target, and its inhibition may sensitize treatment\u2010resistant tumors to cell death and enhance patient survival. The key to clinical success will be to carefully develop more intensive dosing regimens, rationally combine agents, and develop trial designs that prioritize the evaluation of new agents that maximize antitumor activity without the risk of off\u2010target toxicities. Continued translational research and adaptive clinical trials are critical to fully realize the therapeutic potential of MCL\u20101 inhibition across various cancer contexts.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hsr2.71390","type":"journal-article","created":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T05:06:03Z","timestamp":1761109563000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Targeting MCL\u20101 to Overcome Therapeutic Resistance and Improve Cancer Mortality"],"prefix":"10.1002","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7313-8655","authenticated-orcid":false,"given":"Md","family":"Mohiuddin","sequence":"first","affiliation":[{"name":"Department of Pharmacy Southeast University Dhaka Bangladesh"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,10,21]]},"reference":[{"key":"e_1_2_15_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/febs.16136"},{"key":"e_1_2_15_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2018.02.005"},{"key":"e_1_2_15_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-017-0035-2"},{"key":"e_1_2_15_5_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2024.1408107"},{"key":"e_1_2_15_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-021-01079-1"},{"key":"e_1_2_15_7_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2023.1226289"},{"key":"e_1_2_15_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13000-019-0884-3"},{"key":"e_1_2_15_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.699629"},{"key":"e_1_2_15_10_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-18-0140"},{"key":"e_1_2_15_11_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.15962"},{"key":"e_1_2_15_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2024.02.035"},{"key":"e_1_2_15_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-021-02564-6"},{"key":"e_1_2_15_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2020.101015"},{"key":"e_1_2_15_15_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.215855.113"},{"key":"e_1_2_15_16_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020006916"},{"key":"e_1_2_15_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2025.03.013"},{"key":"e_1_2_15_18_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1304105"},{"key":"e_1_2_15_19_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-16-3242"},{"key":"e_1_2_15_20_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells3020418"},{"key":"e_1_2_15_21_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-22-2088"},{"key":"e_1_2_15_22_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.28593"},{"key":"e_1_2_15_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-020-03351-7"},{"issue":"1","key":"e_1_2_15_24_1","first-page":"33","article-title":"Ubiquitin\u2010Proteasome Pathway\u2010Mediated Regulation of the Bcl\u20102 Family: Effects and Therapeutic Approaches","volume":"109","author":"Tang G. 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