BH3 mimetics as anti-fibrotic therapy: Unleashing the mitochondrial pathway of apoptosis in myofibroblasts.

Organs and tissues in mammals can undergo self-repair following injury. However, chronic or severe tissue injury leads to the development of dense scar tissue or fibrosis at the expense of regeneration. The identification of novel therapeutic strategies aiming at reversing fibrosis is therefore a major clinical unmet need in regenerative medicine. Persistent activation of scar-forming myofibroblasts distinguishes non-resolving pathological fibrosis from self-limited physiological wound healing. Thus, therapeutic strategies selectively inducing myofibroblast apoptosis could prevent progression and potentially reverse established fibrosis in fibrotic diseases. In this Review, we discuss recent findings that have demonstrated that activated myofibroblasts, traditionally viewed as apoptosis-resistant cells, are actually "primed for death". In this state, mitochondria of activated myofibroblasts are loaded with proapoptotic BH3 proteins, which creates a cellular "addiction" to individual antiapoptotic proteins to block prodeath signaling and ensure survival. This creates a novel therapeutic opportunity to treat organ fibrosis by inducing myofibroblast apoptosis with the so-called BH3 mimetic drugs, which have recently shown potent antifibrotic activities in experimental models. Finally, we discuss the potential use of BH3 profiling as a functional tool to diagnose myofibroblast addiction to individual antiapoptotic proteins, which may serve to guide and assign the most effective BH3 mimetic drug for patients with fibrotic disease.