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

Lactylation, an emerging posttranslational modification, plays a crucial role in epigenetic regulation and tumorigenesis. Characterization of the key enzymes governing lactylation in tumors, including writers, erasers, and readers, could help identify potential therapeutic targets. In this study, we used lactylome analysis and immunoprecipitation mass spectrometry to identify a role for PARK7 as a delactylase. PARK7 catalyzed the delactylation of the RNA splicing-related protein SF3B2 at lysine 280 (K280), limiting tumor growth in an immune-dependent manner. RNA immunoprecipitation sequencing revealed that the 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 patients with cancer. 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.

PARK7 functions as a delactylase that modifies SF3B2 and inhibits aberrant RNA splicing to suppress fibrosis in an immune-dependent manner, supporting the potential of harnessing this axis to reprogram the tumor microenvironment.