PKIA (cAMP-dependent protein kinase inhibitor alpha) is an extremely potent competitive inhibitor of PKA catalytic activity 1. It functions by interacting with the catalytic subunit of PKA after cAMP-induced dissociation of regulatory chains, thereby suppressing canonical PKA signaling 2. PKIA shows tissue-specific expression, with abundant expression in heart and skeletal muscle 1, and contains functionally critical nuclear export signals and pseudosubstrate sites conserved across PKI family members 13. Mechanistically, PKIA negatively regulates cAMP/PKA signal transduction but can activate noncanonical EPAC-Rap1-ERK pathways when elevated 2. It is regulated post-transcriptionally through miRNA-mediated mechanisms, including the miR-10a-3p/PKIA/RhoA/ROCK axis in smooth muscle 4. DNA methylation status of PKIA serves as an independent prognostic marker 5. PKIA exhibits paradoxical roles in cancer: low expression correlates with poor prognosis in osteosarcoma and lung adenocarcinoma 65, while high expression drives chemoresistance in Ewing sarcoma through cAMP-EPAC signaling 2. PKIA also participates in ceRNA networks affecting hepatocellular carcinoma and osteosarcoma prognosis 76. Therapeutically, PKIA and the cAMP-EPAC pathway represent potential therapeutic targets for overcoming drug resistance in malignancies.