Silica-induced CDK/CDKI dysregulation in alveolar macrophages and its implications in pulmonary fibrosis via altering macrophage fate: A review.

Abstract

Cyclin-dependent kinases (CDKs) and cyclin-dependent kinase inhibitors (CDKIs) are a pair of antagonistic regulators of cell-cycle progression. Both exhibit aberrant expression in silica-exposed alveolar macrophages (AMs), thereby altering cellular fate. Given the central role of AMs in silicosis pathogenesis, silica-induced CDK/CDKI dysregulation likely contributes to the pathogenesis of silicosis. However, the detailed processes have never been systematically described. In this review, we first summarized the origins of AMs and their recruitment to lung tissue following silica exposure. We then introduced the molecular mechanisms by which silica particles induce CDK/CDKI dysregulation in AMs, including their molecular forms, distribution, degradation, and the signaling pathways involved. Subsequently, we reviewed how CDK/CDKI dysregulation affects pulmonary fibrosis by reprogramming macrophage fate, encompassing pyroptosis, apoptosis, ferroptosis, and polarization. Finally, we explored the therapeutic potential, current challenges, and future strategies of targeting CDK/CDKI in silicosis fibrosis. This review focused on the impact of silica-induced CDK/CDKI dysregulation on macrophage fate and function and the underlying regulatory mechanisms. We further evaluated the significance of CDK/CDKI in pulmonary fibrosis, providing a theoretical foundation for the development of novel antifibrotic therapeutic strategies.