{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T16:01:07Z","timestamp":1792080067795,"version":"4.4.0"},"reference-count":194,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T00:00:00Z","timestamp":1760054400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health","award":["R01AR074420"],"award-info":[{"award-number":["R01AR074420"]}]},{"name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health","award":["3R01AR074420-05S1"],"award-info":[{"award-number":["3R01AR074420-05S1"]}]},{"name":"Department of Veterans Affairs, Biomedical Laboratory Research and Development","award":["BX000141"],"award-info":[{"award-number":["BX000141"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The BCL2 family of proteins plays a pivotal role in regulating apoptosis and cellular homeostasis, making them critical therapeutic targets in cancer and other diseases characterized by pathological cell survival. BH3 mimetics, small molecules that selectively inhibit anti-apoptotic BCL2 family members, have achieved significant clinical success, particularly in hematologic malignancies. However, several challenges remain, including resistance mechanisms, toxicity (such as MCL1 inhibitor-associated cardiotoxicity), and the intricate balance between apoptotic and non-apoptotic functions. This review provides a comprehensive overview of BCL2 family biology, the development and clinical application and outcomes of BH3 mimetics, and the emerging resistance mechanism known as double-bolt locking. We also examine strategies to overcome resistance, including combination therapies and immunomodulatory approaches. Beyond oncology, we highlight the expanding therapeutic potential of BH3 mimetics in autoimmune, fibrotic, and infectious diseases, as well as regenerative and anti-aging medicine. Finally, we discuss predictive biomarkers and tissue-specific responses that inform precision therapy. Together, these insights underscore the promise of BH3 mimetics and the need for continued multidisciplinary research to optimize their clinical impact.<\/jats:p>","DOI":"10.3390\/ijms26209859","type":"journal-article","created":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:50:16Z","timestamp":1760107816000},"page":"9859","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Targeting the BCL2 Family: Advances and Challenges in BH3 Mimetic-Based Therapies"],"prefix":"10.3390","volume":"26","author":[{"given":"Nabanita","family":"Mukherjee","sequence":"first","affiliation":[{"name":"Department of Dermatology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Sheetz","sequence":"additional","affiliation":[{"name":"Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0598-5753","authenticated-orcid":false,"given":"Yiqun G.","family":"Shellman","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"},{"name":"Gates Institute, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"},{"name":"Rocky Mountain Regional VA Medical Center, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"eabc4149","DOI":"10.1126\/sciadv.abc4149","article-title":"Ancient and conserved functional interplay between Bcl-2 family proteins in the mitochondrial pathway of apoptosis","volume":"6","author":"Popgeorgiev","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Banjara, S., Suraweera, C.D., Hinds, M.G., and Kvansakul, M. (2020). The Bcl-2 Family: Ancient Origins, Conserved Structures, and Divergent Mechanisms. Biomolecules, 10.","DOI":"10.3390\/biom10010128"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.bbamcr.2003.08.012","article-title":"Structural biology of the Bcl-2 family of proteins","volume":"1644","author":"Petros","year":"2004","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Qian, S., Wei, Z., Yang, W., Huang, J., Yang, Y., and Wang, J. (2022). The role of BCL-2 family proteins in regulating apoptosis and cancer therapy. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.985363"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1007\/978-1-4613-1261-1_3","article-title":"Bcl-2 family proteins and the regulation of programmed cell death in leukemia and lymphoma","volume":"84","author":"Reed","year":"1996","journal-title":"Cancer Treat. Res."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Shamas-Din, A., Kale, J., Leber, B., and Andrews, D.W. (2013). Mechanisms of action of Bcl-2 family proteins. Cold Spring Harb. Perspect. Biol., 5.","DOI":"10.1101\/cshperspect.a008714"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1038\/s41392-025-02176-0","article-title":"The BCL2 family: From apoptosis mechanisms to new advances in targeted therapy","volume":"10","author":"Vogler","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1038\/s41418-025-01481-z","article-title":"The BCL-2 protein family: From discovery to drug development","volume":"32","author":"Croce","year":"2025","journal-title":"Cell Death Differ."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1093\/carcin\/bgx016","article-title":"Non-canonical roles of Bcl-2 and Bcl-xL proteins: Relevance of BH4 domain","volume":"38","author":"Gabellini","year":"2017","journal-title":"Carcinogenesis"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1348","DOI":"10.1038\/ncb1499","article-title":"Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies","volume":"8","author":"Kim","year":"2006","journal-title":"Nat. Cell Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1038\/s41419-020-2417-0","article-title":"BCL-w: Apoptotic and non-apoptotic role in health and disease","volume":"11","author":"Hartman","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1038\/sj.cdd.4400519","article-title":"Survival activity of Bcl-2 homologs Bcl-w and A1 only partially correlates with their ability to bind pro-apoptotic family members","volume":"6","author":"Holmgreen","year":"1999","journal-title":"Cell Death Differ."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"36001","DOI":"10.1074\/jbc.M114.610758","article-title":"The functional differences between pro-survival and pro-apoptotic B cell lymphoma 2 (Bcl-2) proteins depend on structural differences in their Bcl-2 homology 3 (BH3) domains","volume":"289","author":"Lee","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2806","DOI":"10.1182\/blood-2013-08-519470","article-title":"Antiapoptotic potency of Bcl-2 proteins primarily relies on their stability, not binding selectivity","volume":"123","author":"Rooswinkel","year":"2014","journal-title":"Blood"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"404.e1","DOI":"10.1016\/j.cell.2009.07.003","article-title":"SnapShot: BCL-2 proteins","volume":"138","author":"Hardwick","year":"2009","journal-title":"Cell"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Pervushin, N.V., Kopeina, G.S., and Zhivotovsky, B. (2023). Bcl-B: An \u201cunknown\u201d protein of the Bcl-2 family. Biol. Direct, 18.","DOI":"10.1186\/s13062-023-00431-4"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2329","DOI":"10.1093\/hmg\/10.21.2329","article-title":"Bcl2-L-10, a novel anti-apoptotic member of the Bcl-2 family, blocks apoptosis in the mitochondria death pathway but not in the death receptor pathway","volume":"10","author":"Zhang","year":"2001","journal-title":"Hum. Mol. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s43042-024-00485-7","article-title":"Emerging biomarkers and potential therapeutics of the BCL-2 protein family: The apoptotic and anti-apoptotic context","volume":"25","author":"Saddam","year":"2024","journal-title":"Egypt. J. Med. Human Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"267","DOI":"10.4062\/biomolther.2023.149","article-title":"Unlocking the Therapeutic Potential of BCL-2 Associated Protein Family: Exploring BCL-2 Inhibitors in Cancer Therapy","volume":"32","author":"Dakkak","year":"2024","journal-title":"Biomol. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1158\/2159-8290.CD-15-0011","article-title":"The BCL2 Family: Key Mediators of the Apoptotic Response to Targeted Anticancer Therapeutics","volume":"5","author":"Hata","year":"2015","journal-title":"Cancer Discov."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4935","DOI":"10.1074\/jbc.M112.422204","article-title":"Direct Interaction of Bax and Bak Proteins with Bcl-2 Homology Domain 3 (BH3)-only Proteins in Living Cells Revealed by Fluorescence Complementation*","volume":"288","author":"Vela","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1038\/cdd.2017.186","article-title":"BCL-2 family proteins: Changing partners in the dance towards death","volume":"25","author":"Kale","year":"2018","journal-title":"Cell Death Differ."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"jcs260790","DOI":"10.1242\/jcs.260790","article-title":"Expanding roles of BCL-2 proteins in apoptosis execution and beyond","volume":"136","author":"King","year":"2023","journal-title":"J. Cell Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5214","DOI":"10.1073\/pnas.83.14.5214","article-title":"Analysis of the structure, transcripts, and protein products of bcl-2, the gene involved in human follicular lymphoma","volume":"83","author":"Tsujimoto","year":"1986","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.canlet.2011.12.021","article-title":"BH3 profiling--measuring integrated function of the mitochondrial apoptotic pathway to predict cell fate decisions","volume":"332","author":"Letai","year":"2013","journal-title":"Cancer Lett."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.tcb.2012.08.011","article-title":"Delving deeper: MCL-1\u2019s contributions to normal and cancer biology","volume":"23","author":"Perciavalle","year":"2013","journal-title":"Trends Cell Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1517\/13543784.2011.609167","article-title":"Targeting Mcl-1 for the therapy of cancer","volume":"20","author":"Quinn","year":"2011","journal-title":"Expert. Opin. Investig. Drugs"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Tantawy, S.I., Timofeeva, N., Sarkar, A., and Gandhi, V. (2023). Targeting MCL-1 protein to treat cancer: Opportunities and challenges. Front. Oncol., 13.","DOI":"10.3389\/fonc.2023.1226289"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1038\/nature19830","article-title":"The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models","volume":"538","author":"Kotschy","year":"2016","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1016\/j.ccell.2018.11.004","article-title":"BH3-Mimetic Drugs: Blazing the Trail for New Cancer Medicines","volume":"34","author":"Merino","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5167","DOI":"10.1038\/s41467-019-12409-w","article-title":"Targeting melanoma\u2019s MCL1 bias unleashes the apoptotic potential of BRAF and ERK1\/2 pathway inhibitors","volume":"10","author":"Sale","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"100199","DOI":"10.1016\/j.medidd.2024.100199","article-title":"Targeting BCL-2 family proteins using BH3 mimetic drugs for cancer therapy: A systematic review of randomized clinical trials","volume":"24","author":"Alharbi","year":"2024","journal-title":"Med. Drug Discov."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1158\/2159-8290.CD-14-0353","article-title":"Maturation stage of T-cell acute lymphoblastic leukemia determines BCL-2 versus BCL-XL dependence and sensitivity to ABT-199","volume":"4","author":"Chonghaile","year":"2014","journal-title":"Cancer Discov."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1038\/cdd.2015.50","article-title":"The BCL-2 protein family, BH3-mimetics and cancer therapy","volume":"22","author":"Delbridge","year":"2015","journal-title":"Cell Death Differ."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2922","DOI":"10.1021\/acsptsci.5c00088","article-title":"Understanding the Functional Dependence and Inhibition of the Bcl-2 Pro-Survival Proteins in a Wide Spectrum of Cancers toward Precision Medicine","volume":"8","author":"Kump","year":"2025","journal-title":"ACS Pharmacol. Transl. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.beha.2019.05.008","article-title":"Venetoclax-based therapies for acute myeloid leukemia","volume":"32","author":"Guerra","year":"2019","journal-title":"Best. Pract. Res. Clin. Haematol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Lasica, M., and Anderson, M.A. (2021). Review of Venetoclax in CLL, AML and Multiple Myeloma. J. Pers. Med., 11.","DOI":"10.3390\/jpm11060463"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1158\/2159-8290.CD-13-0609","article-title":"Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia","volume":"4","author":"Pan","year":"2014","journal-title":"Cancer Discov."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1056\/NEJMoa1513257","article-title":"Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia","volume":"374","author":"Roberts","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"400","DOI":"10.6004\/jadpro.2022.13.4.4","article-title":"Practical Management of the Venetoclax-Treated Patient in Chronic Lymphocytic Leukemia and Acute Myeloid Leukemia","volume":"13","author":"Waggoner","year":"2022","journal-title":"J. Adv. Pract. Oncol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Glaviano, A., Weisberg, E., Lam, H.Y., Tan, D.J.J., Innes, A.J., Ge, Y., Lai, C.E., Stock, W., Glytsou, C., and Smit, L. (2025). Apoptosis-targeting BH3 mimetics: Transforming treatment for patients with acute myeloid leukaemia. Nat. Rev. Clin. Oncol.","DOI":"10.1038\/s41571-025-01068-0"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1038\/s41419-021-03500-6","article-title":"The application of BH3 mimetics in myeloid leukemias","volume":"12","author":"Parry","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Lin, V.S., Xu, Z.F., Huang, D.C.S., and Thijssen, R. (2020). BH3 Mimetics for the Treatment of B-Cell Malignancies-Insights and Lessons from the Clinic. Cancers, 12.","DOI":"10.3390\/cancers12113353"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4931","DOI":"10.1038\/s41467-025-60238-x","article-title":"BH3 mimetics targeting BCL-XL have efficacy in solid tumors with RB1 loss and replication stress","volume":"16","author":"Varkaris","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1631","DOI":"10.1172\/JCI118202","article-title":"Apoptosis in rheumatoid arthritis synovium","volume":"96","author":"Firestein","year":"1995","journal-title":"J. Clin. Investig."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1200\/JCO.2010.31.6208","article-title":"Phase I study of Navitoclax (ABT-263), a novel Bcl-2 family inhibitor, in patients with small-cell lung cancer and other solid tumors","volume":"29","author":"Gandhi","year":"2011","journal-title":"J. Clin. Oncol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1554","DOI":"10.1007\/s12094-022-03070-9","article-title":"Bcl-2 pathway inhibition in solid tumors: A review of clinical trials","volume":"25","author":"Ploumaki","year":"2023","journal-title":"Clin. Transl. Oncol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2397","DOI":"10.1042\/BST20210750","article-title":"Targeting the BCL-2-regulated apoptotic pathway for the treatment of solid cancers","volume":"49","author":"Fairlie","year":"2021","journal-title":"Biochem. Soc. Trans."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1038\/s41420-025-02379-y","article-title":"Mitochondrial priming and response to BH3 mimetics in \u201cone-two punch\u201d senogenic-senolytic strategies","volume":"11","author":"Verdura","year":"2025","journal-title":"Cell Death Discov."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"El Abbassi, A., Redouane, S., Azoubi, Z., Zougagh, N., Mouslim, A., and Menggad, M. (2025). Screening of the Prodiginine Molecules as BH3-Mimetics against the Developed Bcl-2 Antiapoptotic Chemotherapeutic Resistance: A Molecular Docking and ADMET Study Supported by Molecular Dynamics Simulations. Curr. Comput. Aided Drug Des.","DOI":"10.2174\/0115734099367809250407094437"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1016\/j.chembiol.2016.07.022","article-title":"Selective Covalent Targeting of Anti-Apoptotic BFL-1 by Cysteine-Reactive Stapled Peptide Inhibitors","volume":"23","author":"Huhn","year":"2016","journal-title":"Cell Chem. Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1042\/BST20220153","article-title":"Last but not least: BFL-1 as an emerging target for anti-cancer therapies","volume":"50","author":"Wang","year":"2022","journal-title":"Biochem. Soc. Trans."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1056\/NEJMoa2012971","article-title":"Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia","volume":"383","author":"DiNardo","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2137","DOI":"10.1182\/blood.2020004856","article-title":"Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: A phase 3 randomized placebo-controlled trial","volume":"135","author":"Wei","year":"2020","journal-title":"Blood"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"564","DOI":"10.2174\/0113892002338926241114080504","article-title":"Clinical Pharmacology and Side Effects of Venetoclax in Hematologic Malignancies","volume":"25","author":"Yan","year":"2025","journal-title":"Curr. Drug Metab."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1182\/bloodadvances.2023011964","article-title":"Risk of infectious adverse events of venetoclax therapy for hematologic malignancies: A systematic review and meta-analysis of RCTs","volume":"8","author":"Prosty","year":"2024","journal-title":"Blood Adv."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1038\/s41419-019-1568-3","article-title":"BCL-XL and MCL-1 are the key BCL-2 family proteins in melanoma cell survival","volume":"10","author":"Lee","year":"2019","journal-title":"Cell Death Dis."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Mukherjee, N., Amato, C.M., Skees, J., Todd, K.J., Lambert, K.A., Robinson, W.A., Van Gulick, R., Weight, R.M., Dart, C.R., and Tobin, R.P. (2020). Simultaneously Inhibiting BCL2 and MCL1 Is a Therapeutic Option for Patients with Advanced Melanoma. Cancers, 12.","DOI":"10.3390\/cancers12082182"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1038\/s41419-020-2646-2","article-title":"MCL1 inhibitors S63845\/MIK665 plus Navitoclax synergistically kill difficult-to-treat melanoma cells","volume":"11","author":"Mukherjee","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1016\/S1470-2045(10)70261-8","article-title":"Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: A phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity","volume":"11","author":"Wilson","year":"2010","journal-title":"Lancet Oncol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1080\/10428194.2020.1845332","article-title":"Safety and efficacy of navitoclax, a BCL-2 and BCL-X(L) inhibitor, in patients with relapsed or refractory lymphoid malignancies: Results from a phase 2a study","volume":"62","author":"Leonard","year":"2021","journal-title":"Leuk. Lymphoma"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1158\/1078-0432.CCR-23-3135","article-title":"Phase I\/II Study of Combined BCL-xL and MEK Inhibition with Navitoclax and Trametinib in KRAS or NRAS Mutant Advanced Solid Tumors","volume":"30","author":"Corcoran","year":"2024","journal-title":"Clin. Cancer Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"101015","DOI":"10.1016\/j.isci.2020.101015","article-title":"MCL-1 Inhibition by Selective BH3 Mimetics Disrupts Mitochondrial Dynamics Causing Loss of Viability and Functionality of Human Cardiomyocytes","volume":"23","author":"Rasmussen","year":"2020","journal-title":"iScience"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"CT172","DOI":"10.1158\/1538-7445.AM2023-CT172","article-title":"Abstract CT172: A phase 1, open-label, dose-escalation study of PRT1419, a selective induced myeloid leukemia cell differentiation protein (MCL-1) inhibitor, in patients (pts) with advanced\/metastatic solid tumors","volume":"83","author":"Falchook","year":"2023","journal-title":"Cancer Res."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Chaulin, A.M. (2023). The Essential Strategies to Mitigate Cardiotoxicity Caused by Doxorubicin. Life, 13.","DOI":"10.3390\/life13112148"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.1038\/s43018-024-00814-0","article-title":"BRD-810 is a highly selective MCL1 inhibitor with optimized in vivo clearance and robust efficacy in solid and hematological tumor models","volume":"5","author":"Rauh","year":"2024","journal-title":"Nat. Cancer"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"104376","DOI":"10.1016\/j.drudis.2025.104376","article-title":"PROTAC 2.0: Expanding the frontiers of targeted protein degradation","volume":"30","author":"Cornu","year":"2025","journal-title":"Drug Discov. Today"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.2217\/nnm-2021-0059","article-title":"BH3 mimetics in cancer therapy and their future perspectives with nanodelivery","volume":"16","author":"Mehrotra","year":"2021","journal-title":"Nanomedicine"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"100712","DOI":"10.1016\/j.drup.2020.100712","article-title":"Inhibiting the inhibitors: Targeting anti-apoptotic proteins in cancer and therapy resistance","volume":"52","author":"Shahar","year":"2020","journal-title":"Drug Resist. Updat."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Liu, J., Chen, Y., Yu, L., and Yang, L. (2022). Mechanisms of venetoclax resistance and solutions. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.1005659"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2488","DOI":"10.1182\/blood.2024028239","article-title":"A CEBPB\/IL-1beta\/TNF-alpha feedback loop drives drug resistance to venetoclax and MDM2 inhibitors in monocytic leukemia","volume":"145","author":"Allen","year":"2025","journal-title":"Blood"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"6815","DOI":"10.1158\/1078-0432.CCR-19-0832","article-title":"Inhibition of Bcl-2 Synergistically Enhances the Antileukemic Activity of Midostaurin and Gilteritinib in Preclinical Models of FLT3-Mutated Acute Myeloid Leukemia","volume":"25","author":"Ma","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1038\/s43018-020-0103-x","article-title":"Integrated analysis of patient samples identifies biomarkers for venetoclax efficacy and combination strategies in acute myeloid leukemia","volume":"1","author":"Zhang","year":"2020","journal-title":"Nat. Cancer"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1038\/s41392-021-00578-4","article-title":"FLT3 tyrosine kinase inhibitors synergize with BCL-2 inhibition to eliminate FLT3\/ITD acute leukemia cells through BIM activation","volume":"6","author":"Zhu","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"380","DOI":"10.20517\/cdr.2021.125","article-title":"Venetoclax resistance: Mechanistic insights and future strategies","volume":"5","author":"Ong","year":"2022","journal-title":"Cancer Drug Resist."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"eadh1436","DOI":"10.1126\/sciadv.adh1436","article-title":"Enhanced TP53 reactivation disrupts MYC transcriptional program and overcomes venetoclax resistance in acute myeloid leukemias","volume":"9","author":"Nishida","year":"2023","journal-title":"Sci. Adv."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1182\/bloodadvances.2024014446","article-title":"Acquired BCL2 variants associated with venetoclax resistance in acute myeloid leukemia","volume":"9","author":"Brown","year":"2025","journal-title":"Blood Adv."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Chatzilygeroudi, T., Karantanos, T., and Pappa, V. (2025). Unraveling Venetoclax Resistance: Navigating the Future of HMA\/Venetoclax-Refractory AML in the Molecular Era. Cancers, 17.","DOI":"10.3390\/cancers17091586"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1038\/s41419-024-06810-7","article-title":"Venetoclax therapy and emerging resistance mechanisms in acute myeloid leukaemia","volume":"15","author":"Nwosu","year":"2024","journal-title":"Cell Death Dis."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Hafezi, S., and Rahmani, M. (2021). Targeting BCL-2 in Cancer: Advances, Challenges, and Perspectives. Cancers, 13.","DOI":"10.3390\/cancers13061292"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"e20231143","DOI":"10.1084\/jem.20231143","article-title":"SETD1B mutations confer apoptosis resistance and BCL2 independence in B cell lymphoma","volume":"221","author":"Portelinha","year":"2024","journal-title":"J. Exp. Med."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1038\/s41419-024-06995-x","article-title":"CRISPR screen of venetoclax response-associated genes identifies transcription factor ZNF740 as a key functional regulator","volume":"15","author":"Zhang","year":"2024","journal-title":"Cell Death Dis."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1182\/blood-2020-141684","article-title":"RNA Cytosine Methyltransferases NSUN1 and NSUN2 Mediate the Lineage-Associated Resistance to Venetoclax in Leukemia","volume":"136","author":"Wood","year":"2020","journal-title":"Blood"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"e70025","DOI":"10.1002\/jimd.70025","article-title":"CLPB Deficiency, a Mitochondrial Chaperonopathy With Neutropenia and Neurological Presentation","volume":"48","author":"Mroz","year":"2025","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1158\/2159-8290.CD-19-0117","article-title":"Targeting Mitochondrial Structure Sensitizes Acute Myeloid Leukemia to Venetoclax Treatment","volume":"9","author":"Chen","year":"2019","journal-title":"Cancer Discov."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"7115","DOI":"10.1074\/jbc.M116.762567","article-title":"The short variant of the mitochondrial dynamin OPA1 maintains mitochondrial energetics and cristae structure","volume":"292","author":"Lee","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1656","DOI":"10.1158\/2159-8290.CD-22-0601","article-title":"Mitophagy Promotes Resistance to BH3 Mimetics in Acute Myeloid Leukemia","volume":"13","author":"Glytsou","year":"2023","journal-title":"Cancer Discov."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1126\/science.1231031","article-title":"PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria","volume":"340","author":"Chen","year":"2013","journal-title":"Science"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1038\/cdd.2009.28","article-title":"PUMA- and Bax-induced autophagy contributes to apoptosis","volume":"16","author":"Yee","year":"2009","journal-title":"Cell Death Differ."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1158\/2159-8290.CD-20-1851","article-title":"An In Vivo CRISPR Screening Platform for Prioritizing Therapeutic Targets in AML","volume":"12","author":"Lin","year":"2022","journal-title":"Cancer Discov."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1038\/s41375-023-01879-z","article-title":"Targeting a mitochondrial E3 ubiquitin ligase complex to overcome AML cell-intrinsic Venetoclax resistance","volume":"37","author":"Nakao","year":"2023","journal-title":"Leukemia"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1016\/j.ccell.2018.10.005","article-title":"Inhibition of Amino Acid Metabolism Selectively Targets Human Leukemia Stem Cells","volume":"34","author":"Jones","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1038\/s43018-020-00126-z","article-title":"Fatty acid metabolism underlies venetoclax resistance in acute myeloid leukemia stem cells","volume":"1","author":"Stevens","year":"2020","journal-title":"Nat. Cancer"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1821","DOI":"10.1038\/s41467-024-45916-6","article-title":"Comprehensive characterization of IFNgamma signaling in acute myeloid leukemia reveals prognostic and therapeutic strategies","volume":"15","author":"Wang","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"e37689","DOI":"10.7554\/eLife.37689","article-title":"Bim escapes displacement by BH3-mimetic anti-cancer drugs by double-bolt locking both Bcl-XL and Bcl-2","volume":"8","author":"Liu","year":"2019","journal-title":"Elife"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"5709","DOI":"10.1038\/s41467-023-41229-2","article-title":"ABCC1 and glutathione metabolism limit the efficacy of BCL-2 inhibitors in acute myeloid leukemia","volume":"14","author":"Ebner","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1294","DOI":"10.1101\/gad.1304105","article-title":"Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins","volume":"19","author":"Willis","year":"2005","journal-title":"Genes. Dev."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"653","DOI":"10.18632\/oncotarget.28440","article-title":"Decoding the mechanism behind MCL-1 inhibitors: A pathway to understanding MCL-1 protein stability","volume":"14","author":"Tantawy","year":"2023","journal-title":"Oncotarget"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1038\/s41418-023-01117-0","article-title":"Lymphoma cells lacking pro-apoptotic BAX are highly resistant to BH3-mimetics targeting pro-survival MCL-1 but retain sensitivity to conventional DNA-damaging drugs","volume":"30","author":"Diepstraten","year":"2023","journal-title":"Cell Death Differ."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1582","DOI":"10.1158\/2159-8290.CD-18-0387","article-title":"AMG 176, a Selective MCL1 Inhibitor, Is Effective in Hematologic Cancer Models Alone and in Combination with Established Therapies","volume":"8","author":"Caenepeel","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1016\/j.ccr.2012.02.028","article-title":"Chemical genomics identifies small-molecule MCL1 repressors and BCL-xL as a predictor of MCL1 dependency","volume":"21","author":"Wei","year":"2012","journal-title":"Cancer Cell"},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"M\u00fcller, D., Mazzeo, P., Koch, R., B\u00f6sherz, M.-S., Welter, S., von Hammerstein-Equord, A., Hinterthaner, M., Cordes, L., Belharazem, D., and Marx, A. (2021). Functional apoptosis profiling identifies MCL-1 and BCL-xL as prognostic markers and therapeutic targets in advanced thymomas and thymic carcinomas. BMC Med., 19.","DOI":"10.1186\/s12916-021-02158-3"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1038\/s41419-023-06231-y","article-title":"The identification of BCL-XL and MCL-1 as key anti-apoptotic proteins in medulloblastoma that mediate distinct roles in chemotherapy resistance","volume":"14","author":"Fitzgerald","year":"2023","journal-title":"Cell Death Dis."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41420-022-01296-8","article-title":"Co-targeting BCL-XL and MCL-1 with DT2216 and AZD8055 synergistically inhibit small-cell lung cancer growth without causing on-target toxicities in mice","volume":"9","author":"Khan","year":"2023","journal-title":"Cell Death Discov."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1912","DOI":"10.1016\/j.jid.2021.11.035","article-title":"Expression Differences in BCL2 Family Members between Uveal and Cutaneous Melanomas Account for Varying Sensitivity to BH3 Mimetics","volume":"142","author":"Mukherjee","year":"2022","journal-title":"J. Investig. Dermatol."},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Opydo, M., Mlyczy\u0144ska, A., Mlyczy\u0144ska, E., Rak, A., and Kolaczkowska, E. (2023). Synergistic Action of MCL-1 Inhibitor with BCL-2\/BCL-XL or MAPK Pathway Inhibitors Enhances Acute Myeloid Leukemia Cell Apoptosis and Differentiation. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24087180"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1566","DOI":"10.1158\/2159-8290.CD-18-0140","article-title":"A Novel MCL1 Inhibitor Combined with Venetoclax Rescues Venetoclax-Resistant Acute Myelogenous Leukemia","volume":"8","author":"Ramsey","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/s41392-025-02125-x","article-title":"Src inhibition potentiates MCL-1 antagonist activity in acute myeloid leukemia","volume":"10","author":"Hu","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/j.ccr.2006.03.027","article-title":"Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members","volume":"9","author":"Certo","year":"2006","journal-title":"Cancer Cell"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1038\/s41418-025-01454-2","article-title":"Deciphering molecular specificity in MCL-1\/BAK interaction and its implications for designing potent MCL-1 inhibitors","volume":"32","author":"Wei","year":"2025","journal-title":"Cell Death Differ."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"5228","DOI":"10.1182\/blood-2010-03-275925","article-title":"Follicular dendritic cell-dependent drug resistance of non-Hodgkin lymphoma involves cell adhesion-mediated Bim down-regulation through induction of microRNA-181a","volume":"116","author":"Lwin","year":"2010","journal-title":"Blood"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1182\/blood-2011-01-327197","article-title":"Distribution of Bim determines Mcl-1 dependence or codependence with Bcl-xL\/Bcl-2 in Mcl-1-expressing myeloma cells","volume":"118","author":"Morales","year":"2011","journal-title":"Blood"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"e54954","DOI":"10.7554\/eLife.54954","article-title":"MARCH5 mediates NOXA-dependent MCL1 degradation driven by kinase inhibitors and integrated stress response activation","volume":"9","author":"Arai","year":"2020","journal-title":"eLife"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"5157","DOI":"10.1038\/s41467-019-12477-y","article-title":"Destabilization of NOXA mRNA as a common resistance mechanism to targeted therapies","volume":"10","author":"Montero","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1038\/s41467-020-14392-z","article-title":"Overcoming MCL-1-driven adaptive resistance to targeted therapies","volume":"11","author":"Wood","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_116","doi-asserted-by":"crossref","unstructured":"Widden, H., and Placzek, W.J. (2021). The multiple mechanisms of MCL1 in the regulation of cell fate. Commun. Biol., 4.","DOI":"10.1038\/s42003-021-02564-6"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1038\/s41392-021-00870-3","article-title":"Activation of RAS\/MAPK pathway confers MCL-1 mediated acquired resistance to BCL-2 inhibitor venetoclax in acute myeloid leukemia","volume":"7","author":"Zhang","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1007\/s10495-022-01756-7","article-title":"c-Myc plays a critical role in the antileukemic activity of the Mcl-1-selective inhibitor AZD5991 in acute myeloid leukemia","volume":"27","author":"Liu","year":"2022","journal-title":"Apoptosis"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"58","DOI":"10.3324\/haematol.2020.260331","article-title":"Targeting MCL-1 dysregulates cell metabolism and leukemia-stroma interactions and resensitizes acute myeloid leukemia to BCL-2 inhibition","volume":"107","author":"Carter","year":"2022","journal-title":"Haematologica"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1290","DOI":"10.1038\/leu.2015.18","article-title":"Mutated Ptpn11 alters leukemic stem cell frequency and reduces the sensitivity of acute myeloid leukemia cells to Mcl1 inhibition","volume":"29","author":"Chen","year":"2015","journal-title":"Leukemia"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"4125","DOI":"10.1182\/bloodadvances.2020003826","article-title":"Heterogeneous modulation of Bcl-2 family members and drug efflux mediate MCL-1 inhibitor resistance in multiple myeloma","volume":"5","author":"Bolomsky","year":"2021","journal-title":"Blood Adv."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1002\/pro.329","article-title":"Mcl-1-Bim complexes accommodate surprising point mutations via minor structural changes","volume":"19","author":"Fire","year":"2010","journal-title":"Protein Sci."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/S0092-8674(02)00762-6","article-title":"Bcl2 regulation by the melanocyte master regulator Mitf modulates lineage survival and melanoma cell viability","volume":"109","author":"McGill","year":"2002","journal-title":"Cell"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"4321","DOI":"10.1073\/pnas.1205575110","article-title":"BCL2A1 is a lineage-specific antiapoptotic melanoma oncogene that confers resistance to BRAF inhibition","volume":"110","author":"Haq","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.1182\/blood.2020006785","article-title":"BCL2 and MCL1 inhibitors for hematologic malignancies","volume":"138","author":"Roberts","year":"2021","journal-title":"Blood"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"4844","DOI":"10.1158\/1078-0432.CCR-24-0028","article-title":"A Phase 1 First-in-Human Study of the MCL-1 Inhibitor AZD5991 in Patients with Relapsed\/Refractory Hematologic Malignancies","volume":"30","author":"Desai","year":"2024","journal-title":"Clin. Cancer Res."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1097\/CAD.0000000000001553","article-title":"Dual targeting of Mcl-1 and Bcl-2 to overcome chemoresistance in cervical and colon cancer","volume":"35","author":"Wang","year":"2024","journal-title":"Anticancer. Drugs"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"10795","DOI":"10.1021\/acs.jmedchem.4c00291","article-title":"Discovery of a Covalent Inhibitor That Overcame Resistance to Venetoclax in AML Cells Overexpressing BFL-1","volume":"67","author":"Lou","year":"2024","journal-title":"J. Med. Chem."},{"key":"ref_129","doi-asserted-by":"crossref","unstructured":"Gelmi, M.C., Houtzagers, L.E., Strub, T., Krossa, I., and Jager, M.J. (2022). MITF in Normal Melanocytes, Cutaneous and Uveal Melanoma: A Delicate Balance. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23116001"},{"key":"ref_130","doi-asserted-by":"crossref","unstructured":"Hartman, M.L., Sztiller-Sikorska, M., and Czyz, M. (2025). Synergistic activity of S63845 and parthenolide to overcome acquired resistance to MEK1\/2 inhibitor in melanoma cells: Mechanisms and therapeutic potential. Biomed. Pharmacother., 188.","DOI":"10.1016\/j.biopha.2025.118183"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"107547","DOI":"10.1016\/j.leukres.2024.107547","article-title":"Combining the novel FLT3 and MERTK dual inhibitor MRX-2843 with venetoclax results in promising antileukemic activity against FLT3-ITD AML","volume":"144","author":"Wu","year":"2024","journal-title":"Leuk. Res."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"102467","DOI":"10.1016\/j.tranon.2025.102467","article-title":"Sitravatinib combined with venetoclax exerts effective synergy to eliminate acute myeloid leukemia cells with FLT3-ITD mutations","volume":"59","author":"Yang","year":"2025","journal-title":"Transl. Oncol."},{"key":"ref_133","doi-asserted-by":"crossref","unstructured":"Cui, Y., Shao, X., Yang, H., Xin, J., Liu, Y., Zhang, M., Sun, C., Chen, G., Shen, G., and Meng, X. (2024). MDM2 inhibitor APG-115 synergizes with ABT-199 to induce cell apoptosis in chronic lymphocytic leukemia. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1441383"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1007\/s12288-022-01584-4","article-title":"The Impact of Panobinostat on Cell Death in Combination with S63845 in Multiple Myeloma Cells","volume":"39","author":"Tagoug","year":"2023","journal-title":"Indian. J. Hematol. Blood Transfus."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.neo.2021.11.012","article-title":"Selective BH3 mimetics synergize with BET inhibition to induce mitochondrial apoptosis in rhabdomyosarcoma cells","volume":"24","author":"Erdogdu","year":"2022","journal-title":"Neoplasia"},{"key":"ref_136","doi-asserted-by":"crossref","unstructured":"Sasi, B.K., Tarantelli, C., Martindale, S., Civanelli, E., Cannas, E., Sartori, G., Arribas, A.J., Fernandes, S.M., Shupe, S.J., and Machado, J.H. (2025). Novel PI3kdelta inhibitor roginolisib synergizes with venetoclax in hematologic malignancies. Haematologica.","DOI":"10.3324\/haematol.2024.287180"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"4757","DOI":"10.1182\/bloodadvances.2024015322","article-title":"BH3 mimetic drugs overcome the microenvironment-induced resistance to crizotinib in ALK+ anaplastic large cell lymphoma","volume":"9","author":"Pignataro","year":"2025","journal-title":"Blood Adv."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"e70055","DOI":"10.1002\/hon.70055","article-title":"Targeting of PIM Kinases Shows Single Agent Efficacy and Synergizes With BCL2 Inhibitors in Diffuse Large B Cell Lymphoma of the ABC Subtype","volume":"43","author":"Tarantelli","year":"2025","journal-title":"Hematol. Oncol."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/s41389-025-00569-y","article-title":"GSK-3 and BCL-XL inhibition mitigates the competitive advantage of APC-mutant colorectal cancer cells","volume":"14","author":"Zhang","year":"2025","journal-title":"Oncogenesis"},{"key":"ref_140","first-page":"2343","article-title":"Simultaneous inhibition of Sirtuin 3 and cholesterol homeostasis targets acute myeloid leukemia stem cells by perturbing fatty acid beta-oxidation and inducing lipotoxicity","volume":"108","author":"Ling","year":"2023","journal-title":"Haematologica"},{"key":"ref_141","doi-asserted-by":"crossref","unstructured":"Hurrish, K.H., Su, Y., Patel, S., Ramage, C.L., Zhao, J., Temby, B.R., Carter, J.L., Edwards, H., Buck, S.A., and Wiley, S.E. (2024). Enhancing anti-AML activity of venetoclax by isoflavone ME-344 through suppression of OXPHOS and\/or purine biosynthesis in vitro. Biochem. Pharmacol., 220.","DOI":"10.1016\/j.bcp.2023.115981"},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"7433","DOI":"10.1182\/bloodadvances.2023010964","article-title":"Inhibition of glutaminase-1 in DLBCL potentiates venetoclax-induced antitumor activity by promoting oxidative stress","volume":"7","author":"Horn","year":"2023","journal-title":"Blood Adv."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1158\/2159-8290.CD-19-0759","article-title":"Venetoclax Increases Intratumoral Effector T Cells and Antitumor Efficacy in Combination with Immune Checkpoint Blockade","volume":"11","author":"Kohlhapp","year":"2021","journal-title":"Cancer Discov."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1038\/s41423-023-01112-y","article-title":"The BCL-2 inhibitor APG-2575 resets tumor-associated macrophages toward the M1 phenotype, promoting a favorable response to anti-PD-1 therapy via NLRP3 activation","volume":"21","author":"Luo","year":"2024","journal-title":"Cell Mol. Immunol."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1038\/s41419-024-06524-w","article-title":"MCL1 inhibition targets Myeloid Derived Suppressors Cells, promotes antitumor immunity and enhances the efficacy of immune checkpoint blockade","volume":"15","author":"Mukherjee","year":"2024","journal-title":"Cell Death Dis."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1002\/hon.3009","article-title":"Anti-CD47 immunotherapy in combination with BCL-2 inhibitor to enhance anti-tumor activity in B-cell lymphoma","volume":"40","author":"Li","year":"2022","journal-title":"Hematol. Oncol."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1002\/cncr.34566","article-title":"Triple combination targeting methyltransferase, BCL-2, and PD-1 facilitates antileukemia responses in acute myeloid leukemia","volume":"129","author":"Zeng","year":"2023","journal-title":"Cancer"},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.1016\/j.jid.2023.01.017","article-title":"IFN-gamma Signaling Sensitizes Melanoma Cells to BH3 Mimetics","volume":"143","author":"Ming","year":"2023","journal-title":"J. Investig. Dermatol."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1016\/j.ccell.2024.04.004","article-title":"Putting the STING back into BH3-mimetic drugs for TP53-mutant blood cancers","volume":"42","author":"Diepstraten","year":"2024","journal-title":"Cancer Cell"},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"4896","DOI":"10.1016\/j.cell.2025.06.023","article-title":"Combination antiretroviral therapy and MCL-1 inhibition mitigate HTLV-1 infection in vivo","volume":"188","author":"Cooney","year":"2025","journal-title":"Cell"},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"2372","DOI":"10.1158\/2159-8290.CD-21-1026","article-title":"Modulation of BCL-2 in Both T Cells and Tumor Cells to Enhance Chimeric Antigen Receptor T-cell Immunotherapy against Cancer","volume":"12","author":"Lee","year":"2022","journal-title":"Cancer Discov."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1016\/j.cell.2022.03.030","article-title":"Augmenting NK cell-based immunotherapy by targeting mitochondrial apoptosis","volume":"185","author":"Pan","year":"2022","journal-title":"Cell"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1038\/s41420-025-02375-2","article-title":"BH3 mimetics augment cytotoxic T cell killing of acute myeloid leukemia via mitochondrial apoptotic mechanism","volume":"11","author":"Saxena","year":"2025","journal-title":"Cell Death Discov."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1016\/j.ccell.2024.03.003","article-title":"Single-cell systems pharmacology identifies development-driven drug response and combination therapy in B cell acute lymphoblastic leukemia","volume":"42","author":"Huang","year":"2024","journal-title":"Cancer Cell"},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"e31630","DOI":"10.1002\/pbc.31630","article-title":"Venetoclax Combined With Chemotherapy in Pediatric and Adolescent\/Young Adult Patients With Relapsed\/Refractory Acute Lymphoblastic Leukemia","volume":"72","author":"Place","year":"2025","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"1870","DOI":"10.1182\/blood.2024026700","article-title":"Venetoclax plus daunorubicin and cytarabine for newly diagnosed acute myeloid leukemia: Results of a phase 1b study","volume":"145","author":"Mantzaris","year":"2025","journal-title":"Blood"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1038\/s41420-021-00505-0","article-title":"A novel BH3-mimetic, AZD0466, targeting BCL-XL and BCL-2 is effective in pre-clinical models of malignant pleural mesothelioma","volume":"7","author":"Arulananda","year":"2021","journal-title":"Cell Death Discov."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"1823","DOI":"10.1111\/cas.70072","article-title":"Dual Targeting of Aurora-A and Bcl-xL Synergistically Reshapes the Immune Microenvironment and Induces Apoptosis in Breast Cancer","volume":"116","author":"Liu","year":"2025","journal-title":"Cancer Sci."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1016\/S0952-7915(00)00168-0","article-title":"Apoptosis genes and autoimmunity","volume":"12","author":"Vaux","year":"2000","journal-title":"Curr. Opin. Immunol."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"R31","DOI":"10.1186\/ar4179","article-title":"IL-17-mediated Bcl-2 expression regulates survival of fibroblast-like synoviocytes in rheumatoid arthritis through STAT3 activation","volume":"15","author":"Lee","year":"2013","journal-title":"Arthritis Res. Ther."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1093\/rheumatology\/35.7.611","article-title":"Expression of bcl-2 in rheumatoid arthritis","volume":"35","author":"Punnonen","year":"1996","journal-title":"Br. J. Rheumatol."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1002\/art.27198","article-title":"Bim-Bcl-2 homology 3 mimetic therapy is effective at suppressing inflammatory arthritis through the activation of myeloid cell apoptosis","volume":"62","author":"Scatizzi","year":"2010","journal-title":"Arthritis Rheum."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"S168","DOI":"10.1038\/onc.2009.54","article-title":"BH3-only proteins in rheumatoid arthritis: Potential targets for therapeutic intervention","volume":"27","author":"Hutcheson","year":"2008","journal-title":"Oncogene"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1186\/s13075-023-03203-7","article-title":"Differential expression pattern of Bcl-2 family members in B and T cells in systemic lupus erythematosus and rheumatoid arthritis","volume":"25","author":"Kielbassa","year":"2023","journal-title":"Arthritis Res. Ther."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.1177\/09612033221106302","article-title":"Evaluation of the interaction between anti-apoptotic Bcl-2 protein family mRNA expression and autophagy gene Bcl-1 expression in Egyptian SLE patients","volume":"31","author":"Khalil","year":"2022","journal-title":"Lupus"},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"e202","DOI":"10.1097\/HS9.0000000000000202","article-title":"Refractory Autoimmune Cytopenias Treated With Venetoclax","volume":"3","author":"Gordon","year":"2019","journal-title":"Hemasphere"},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1177\/0961203317719334","article-title":"Safety and pharmacodynamics of venetoclax (ABT-199) in a randomized single and multiple ascending dose study in women with systemic lupus erythematosus","volume":"27","author":"Lu","year":"2018","journal-title":"Lupus"},{"key":"ref_168","doi-asserted-by":"crossref","unstructured":"Antar, S.A., Ashour, N.A., Marawan, M.E., and Al-Karmalawy, A.A. (2023). Fibrosis: Types, Effects, Markers, Mechanisms for Disease Progression, and Its Relation with Oxidative Stress, Immunity, and Inflammation. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24044004"},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.matbio.2018.01.020","article-title":"BH3 mimetics as anti-fibrotic therapy: Unleashing the mitochondrial pathway of apoptosis in myofibroblasts","volume":"68\u201369","author":"Kuehl","year":"2018","journal-title":"Matrix Biol."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"eaal3765","DOI":"10.1126\/scitranslmed.aal3765","article-title":"Targeted apoptosis of myofibroblasts with the BH3 mimetic ABT-263 reverses established fibrosis","volume":"9","author":"Lagares","year":"2017","journal-title":"Sci. Transl. Med."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1002\/hep.29464","article-title":"Targeting senescent cholangiocytes and activated fibroblasts with B-cell lymphoma-extra large inhibitors ameliorates fibrosis in multidrug resistance 2 gene knockout (Mdr2(-\/-)) mice","volume":"67","author":"Moncsek","year":"2018","journal-title":"Hepatology"},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1146\/annurev-pharmtox-051921-115130","article-title":"Pharmacological Induction of Granulocyte Cell Death as Therapeutic Strategy","volume":"63","author":"Kaufmann","year":"2023","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"2555","DOI":"10.4049\/jimmunol.0903656","article-title":"The BH3-mimetic ABT-737 induces mast cell apoptosis in vitro and in vivo: Potential for therapeutics","volume":"185","author":"Karlberg","year":"2010","journal-title":"J. Immunol."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1038\/cdd.2017.154","article-title":"BH3 mimetics efficiently induce apoptosis in mouse basophils and mast cells","volume":"25","author":"Reinhart","year":"2018","journal-title":"Cell Death Differ."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1007\/s00432-021-03827-9","article-title":"Comprehensive characterization of central BCL-2 family members in aberrant eosinophils and their impact on therapeutic strategies","volume":"148","author":"Odinius","year":"2022","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"16","DOI":"10.18632\/aging.206165","article-title":"Topical ABT-263 treatment reduces aged skin senescence and improves subsequent wound healing","volume":"17","author":"Shvedova","year":"2024","journal-title":"Aging"},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1186\/s13287-022-02901-4","article-title":"Clearance of senescent cells with ABT-263 improves biological functions of synovial mesenchymal stem cells from osteoarthritis patients","volume":"13","author":"Miura","year":"2022","journal-title":"Stem Cell Res. Ther."},{"key":"ref_178","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Tang, L.H., Lu, J., Xu, L.M., Cheng, B.L., and Xiong, J.Y. (2021). ABT-263 enhanced bacterial phagocytosis of macrophages in aged mouse through Beclin-1-dependent autophagy. BMC Geriatr., 21.","DOI":"10.1186\/s12877-021-02173-2"},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"1348","DOI":"10.1038\/cdd.2017.22","article-title":"Non-apoptotic functions of BCL-2 family proteins","volume":"24","author":"Gross","year":"2017","journal-title":"Cell Death Differ."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"1338","DOI":"10.1016\/j.molcel.2024.02.035","article-title":"Anti-apoptotic MCL-1 promotes long-chain fatty acid oxidation through interaction with ACSL1","volume":"84","author":"Wright","year":"2024","journal-title":"Mol. Cell"},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1126\/science.adw1836","article-title":"Relative importance of the anti-apoptotic versus apoptosis-unrelated functions of MCL-1 in vivo","volume":"389","author":"Brinkmann","year":"2025","journal-title":"Science"},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"113176","DOI":"10.1016\/j.celrep.2023.113176","article-title":"Targeting MCL-1 triggers DNA damage and an anti-proliferative response independent from apoptosis induction","volume":"42","author":"Adhikary","year":"2023","journal-title":"Cell Rep."},{"key":"ref_183","doi-asserted-by":"crossref","unstructured":"Moyzis, A.G., Lally, N.S., Liang, W., Najor, R.H., and Gustafsson, A.B. (2022). Mcl-1 Differentially Regulates Autophagy in Response to Changes in Energy Status and Mitochondrial Damage. Cells, 11.","DOI":"10.3390\/cells11091469"},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1038\/s41420-024-02112-1","article-title":"The endoplasmic reticulum pool of Bcl-xL prevents cell death through IP3R-dependent calcium release","volume":"10","author":"Gadet","year":"2024","journal-title":"Cell Death Discov."},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"eadr1378","DOI":"10.1126\/sciadv.adr1378","article-title":"Bcl-xL overexpression in T cells preserves muscle mitochondrial structure and function and prevents frailty in old mice","volume":"11","author":"Dromant","year":"2025","journal-title":"Sci. Adv."},{"key":"ref_186","doi-asserted-by":"crossref","unstructured":"Kehr, S., and Vogler, M. (2021). It\u2019s time to die: BH3 mimetics in solid tumors. Biochim. Biophys. Acta Mol. Cell Res., 1868.","DOI":"10.1016\/j.bbamcr.2021.118987"},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"1544","DOI":"10.1038\/s41416-020-0795-9","article-title":"A direct comparison of selective BH3-mimetics reveals BCL-X(L), BCL-2 and MCL-1 as promising therapeutic targets in neuroblastoma","volume":"122","author":"Bierbrauer","year":"2020","journal-title":"Br. J. Cancer"},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1016\/j.ccell.2020.10.010","article-title":"Reduced Mitochondrial Apoptotic Priming Drives Resistance to BH3 Mimetics in Acute Myeloid Leukemia","volume":"38","author":"Bhatt","year":"2020","journal-title":"Cancer Cell"},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1038\/s41419-021-04029-4","article-title":"Dynamic BH3 profiling identifies active BH3 mimetic combinations in non-small cell lung cancer","volume":"12","author":"Potter","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1038\/s41419-018-0932-z","article-title":"BH3 mimetics induce apoptosis independent of DRP-1 in melanoma","volume":"9","author":"Mukherjee","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_191","doi-asserted-by":"crossref","unstructured":"Vera, M.B., Morris-Hanon, O., Nogueiras, G.I., Ripari, L.B., Esquivel, M.I., Perez-Castro, C., Romorini, L., Sevlever, G.E., Scassa, M.E., and Videla-Richardson, G.A. (2022). Noxa and Mcl-1 expression influence the sensitivity to BH3-mimetics that target Bcl-xL in patient-derived glioma stem cells. Sci. Rep., 12.","DOI":"10.1038\/s41598-022-20910-4"},{"key":"ref_192","doi-asserted-by":"crossref","unstructured":"Kinloch, A.J., Rahman, F., Karakas, B., Shahid, M., Lim, B., Bouley, S.J., Walker, J.A., Lee, E.F., Fairlie, W.D., and Kelly, K.R. (2025). Development of a Novel Biomarker Platform for Profiling Key Protein-Protein Interactions to Predict the Efficacy of BH3-Mimetic Drugs. Cancers, 17.","DOI":"10.3390\/cancers17111852"},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1182\/blood.2022016090","article-title":"Acquired mutations in BAX confer resistance to BH3-mimetic therapy in acute myeloid leukemia","volume":"141","author":"Moujalled","year":"2023","journal-title":"Blood"},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1093\/oncolo\/oyac047","article-title":"Circulating Biomarkers for Therapeutic Monitoring of Anti-cancer Agents","volume":"27","author":"Spiliopoulou","year":"2022","journal-title":"Oncologist"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/20\/9859\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:00:59Z","timestamp":1760108459000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/20\/9859"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,10]]},"references-count":194,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["ijms26209859"],"URL":"https:\/\/doi.org\/10.3390\/ijms26209859","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,10]]}}}