Metal-dependent protein phosphatase 1A: A potential therapeutic target in fibrotic disorders

Metal-dependent protein phosphatase 1A (PPM1A), a ubiquitously distributed member of the phosphatase superfamily, serves as a crucial signaling modulator through its capacity to dephosphorylate multiple nodal proteins in cellular transduction pathways. Localized to both cytoplasmic and nuclear compartments, PPM1A has emerged as a central negative regulator of key fibrotic and inflammatory cascades, such as transforming growth factor-β (TGF-β), nuclear factor-kappa-B (NF-κB), and mitogen-activated protein kinase (MAPK) pathways. Substantial evidence demonstrates that PPM1A modulates injury responses by attenuating TGF-β-mediated extracellular matrix (ECM) production, inhibiting fibroblast-to- myofibroblast transformation, and restoring tissue homeostasis across multiple organ systems. Research on its activity and status has positioned it as a promising therapeutic target for fibrotic implications. This review provides a comprehensive overview of structural determinants of PPM1A function, its multifaceted roles in cellular physiology, the pathological consequences of PPM1A dysregulation, and current progress in developing PPM1A-targeted therapies.