HDAC11-Mediated Deacetylation of Triosephosphate Isomerase 1 Promotes Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a type of chronic progressive fibrotic interstitial pneumonia and has a poor prognosis due to the lack of effective treatments. Despite extensive investigations into its molecular and cellular mechanisms, the regulatory mechanism involved remains incompletely understood. Triosephosphate isomerase 1 (TPI1), an enzyme in the glycolytic pathway, has emerged as a key research focus in oncogenesis due to its multifaceted roles in malignant progression. However, its role in IPF has not yet been reported. Here, we report that TPI1 expression was elevated in IPF tissues and in mice with bleomycin-induced pulmonary fibrosis. TPI1 knockdown attenuated IPF progression in vitro and in vivo. Mechanistically, we found that histone deacetylase 11 (HDAC11)-mediated deacetylation of TPI1 K69 was enhanced by transforming growth factor-beta1. Deacetylation of TPI1 K69 enhanced its protein stability by attenuating K48-linked polyubiquitination, which enhanced fibroblast-to-myofibroblast differentiation, cell proliferation, and migration. Notably, we designed and tested the activity of a novel cell-penetrating peptide that increased the acetylation of TPI1 and markedly promoted TPI1 degradation, thereby effectively reducing fibrosis. Together, our findings revealed that targeting TPI1 acetylation is an effective strategy for IPF therapy, and the specific cell-penetrating peptide could prevent IPF by promoting the acetylation of TPI1.