Ac-SDKP Attenuates Silica-Induced Pulmonary Fibrosis by Inhibiting ALKBH1-Mediated m6A Demethylation of miR-129-5p.

Silicosis, one of the most common and severe forms of pneumoconiosis, remains a major occupational health concern worldwide. Given the lack of effective therapies, understanding the underlying molecular mechanisms is urgently needed. Here, we report that ALKB homolog 1 (ALKBH1), an N6-methyladenosine (m6A) demethylase, is upregulated in silica-induced pulmonary fibrosis and plays a pro-fibrotic role. The antifibrotic peptide Ac-SDKP inhibited Alkbh1 expression and alleviated pulmonary fibrosis. Mechanistically, ALKBH1 suppressed the biosynthesis of miR-129-5p by removing m6A modification from pri-miR-129-5p, thereby reducing DGCR8-mediated processing and leading to decreased mature miR-129-5p levels. Ac-SDKP reversed this process, restoring miR-129-5p expression. Functionally, overexpression of miR-129-5p attenuated silica-induced pulmonary fibrosis by suppressing macrophage activation. Collectively, these findings identify the Ac-SDKP-ALKBH1-miR-129-5p axis as a critical regulatory mechanism, with ALKBH1-mediated m6A demethylation of pri-miR-129-5p representing a key node and a promising therapeutic target for silicosis.