Myofibroblast apoptosis

Myofibroblast apoptosis is a fundamental biological process required for the resolution of tissue repair and the maintenance of normal organ architecture [1]. Myofibroblasts are specialized, activated cells characterized by alpha-smooth muscle actin (alpha-SMA) expression that synthesize the extracellular matrix (ECM) necessary for wound closure [2]. In physiological healing, these cells undergo programmed cell death once the wound is resolved; however, in chronic fibrotic diseases like idiopathic pulmonary fibrosis and liver cirrhosis, myofibroblasts develop resistance to apoptosis, leading to persistent ECM deposition and organ dysfunction [1, 3]. Therapeutic strategies currently focus on inducing myofibroblast apoptosis to reverse established fibrosis rather than merely slowing its progression [4]. This is often pursued by targeting anti-apoptotic proteins such as BCL-2 and BCL-XL or by inhibiting upstream survival signals like TGF-beta and the PI3K/AKT axis [2, 5]. While drugs like Navitoclax (a BH3 mimetic) have demonstrated the ability to selectively eliminate resistant myofibroblasts in preclinical models, maintaining therapeutic selectivity to avoid systemic side effects, such as thrombocytopenia, remains a significant challenge [1, 4]. Sources: [1] Hinz, B., & Lagares, D. (2020). Nature Reviews Rheumatology. [2] Lagares, et al. (2017). Science Translational Medicine. [3] Hecker, et al. (2014). Science Translational Medicine. [4] Montero, et al. (2015). Journal of Clinical Investigation. [5] Sanders, et al. (2016). European Respiratory Journal.

Other names

Programmed myofibroblast deathMyofibroblast clearanceInduction of myofibroblast apoptosisFibroblast-to-myofibroblast transition reversal

Induction of myofibroblast apoptosis is achieved by antagonizing anti-apoptotic BCL-2 family proteins (e.g., BCL-2, BCL-XL) with BH3 mimetics, inhibiting survival signaling through the TGF-beta or PI3K/AKT pathways, or modulating oxidative stress markers like NOX4 to reverse apoptosis resistance.