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

Lactylation, an emerging post-translational modification, plays a crucial role in epigenetic regulation and tumorigenesis. However, the key enzymes governing lactylation, including writer, eraser and reader, and their effects on tumors remain poorly characterized. Here, using lactylome analysis and immunoprecipitation-Mass Spectrometry (IP-MS), we identified Parkinsonism-associated Protein (PARK7) as a novel delactylase. PARK7 catalyzes the delactylation of RNA splicing-related protein SF3B2 at lysine 280 (K280), limiting tumor growth in an immunity-dependent manner. RNA immunoprecipitation sequencing (RIP-seq) 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 correlates with longer survival among cancer patients. Our findings not only identify a delactylation modification enzyme, PARK7, with tumor-suppressive effects, but also reveal a previously unrecognized connection between lactylation and RNA splicing regulation in cancer biology.