Document Type

Article

Publication Date

10-10-2025

Comments

This article is the author’s final published version in International Journal of Molecular Sciences, Volume 26, Issue 20, 2025, Article number 9859.

The published version is available at https://doi.org/10.3390/ijms26209859. Copyright © 2025 by the authors.

Abstract

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.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

Language

English

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