HDAC8-mediated CAPZB desuccinylation enhances cytoskeleton remodeling to promote idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease of unknown etiology, characterized by progressive scarring and fibrosis of the lungs, leading to irreversible loss of lung function. Current mechanism studies have found that fibroblasts, as the main effector cells, exhibit abnormal differentiation and proliferation in pulmonary fibrosis, thereby promoting collagen secretion for extracellular matrix (ECM) deposition. Cytoskeletal remodeling is the basis for fibroblast-to-myofibroblast differentiation, however, the key proteins and regulatory mechanisms involved in this process are still unclear. Here, F-actin-capping protein subunit beta (CAPZB) was identified to be desuccinylated at three lysine residues (K57, K95, and K235). Gain- and loss-of-function studies in vitro and in vivo demonstrated that CAPZB regulates cytoskeletal remodeling and differentiation of fibroblasts to myofibroblasts by capping the barbed end of F-actin, and mutation of the modification site confirmed the inhibition of CAPZB function by desuccinylation. Further studies showed that histone deacetylase enzymes 8 (HDAC8) could interacts with CAPZB, and its pro-fibrotic role as a desuccinylase was verified. Our findings suggested that desuccinylation inhibited CAPZB function and promoted cytoskeletal remodeling, targeting the succinylation modification of CAPZB could potentially serve as a novel therapeutic approach for pulmonary fibrosis.