RPS6KA1 encodes ribosomal protein S6 kinase A1 (RSK1), a serine/threonine kinase that serves as a critical mediator of cellular growth and metabolic signaling downstream of mTORC1. The primary function involves phosphorylating key substrates to regulate transcriptional programs controlling metabolism and cell proliferation 1. Mechanistically, RSK1 activates SREBP1 and SREBP2 transcription factors downstream of mTORC1, promoting glycolysis, pentose phosphate pathway, and lipid biosynthesis 1. RSK1 also directly phosphorylates TRIM28 at S473, driving a positive feedback loop with E2F1 that promotes cell cycle progression 2. Disease relevance is significant across multiple cancer types. In acute myeloid leukemia, RSK1 confers resistance to venetoclax/azacitidine therapy and maintains FLT3-ITD protein stability through USP1 deubiquitinase 34. RSK1 promotes castration-resistant prostate cancer progression via the TRIM28/E2F1 axis 2 and hepatocellular carcinoma tumorigenesis through AKT/NF-κB activation 5. Clinical significance includes its overexpression correlating with poor prognosis in head and neck squamous cell carcinoma 6 and myeloproliferative neoplasms 7. RSK1 inhibitors like PMD-026 show therapeutic promise, demonstrating efficacy in multiple leukemia models 47, making RSK1 an attractive therapeutic target across diverse malignancies.