PARK7-Mediated Delactylation of SF3B Reprograms RNA Splicing to Attenuate Fibrosis and Promote Antitumor Immunity

Abstract Lactylation, an emerging post-translational modification, plays a crucial role in epigenetic regulation and tumorigenesis. Characterization of the key enzymes governing lactylation, including writers, erasers, and readers, in tumors could help identify potential therapeutic targets. Here, using lactylome analysis and immunoprecipitation-mass spectrometry, we identified a role for PARK7 as a delactylase. PARK7 catalyzed the delactylation of RNA splicing-related protein SF3B2 at lysine 280 (K280), limiting tumor growth in an immune-dependent manner. RNA immunoprecipitation sequencing revealed that lactylation modification of SF3B drives abnormal splicing of serpin family RNA, resulting in excessive serpin secretion into the extracellular matrix and subsequent tumor fibrosis. Clinically, elevated PARK7 expression correlated with longer survival among cancer patients. These findings not only identify a delactylation modification enzyme, PARK7, with tumor-suppressive effects but also reveal a connection between lactylation and RNA splicing regulation in cancer biology.