PRKACA encodes the catalytic subunit alpha of protein kinase A (PKA), a cAMP-dependent serine/threonine kinase with diverse cellular functions. Primarily, PRKACA phosphorylates downstream substrates to regulate cAMP signaling across multiple tissues. In cardiac tissue, PRKACA expression is controlled by Nsun2-mediated m5C methylation, which promotes its translation and is essential for cardiac homeostasis and normal hypertrophic response to stress 1. Mechanistically, Nsun2 modifies PRKACA mRNA in a YBX1-dependent manner, with ablation of Nsun2 impairing PKA signaling and accelerating heart failure progression 1. Clinically, PRKACA is highly relevant to neoplastic diseases. DNAJB1-PRKACA fusion genes are the pathognomonic driver of fibrolamellar hepatocellular carcinoma (FLC), where the fusion protein inactivates SIK signaling to activate CRTC2-p300-mediated transcriptional reprogramming 2 3. PRKACA/B fusions also characterize intraductal oncocytic papillary neoplasms (IOPNs) of the pancreas and biliary tract, with fusion prevalence of 100% in typical IOPNs and 46% in atypical cases 4. Gene fusions involving PRKACA occur preferentially in extrahepatic cholangiocarcinoma and represent actionable therapeutic targets in KRAS wild-type pancreatic cancers 5 6. Additionally, somatic PRKACA mutations are detected in 43.8% of cortisol-producing adenomas presenting with overt Cushing syndrome 7.