A Novel Function of the Branched-Chain Fatty Acid iso15:0 in Suppressing HCC Malignant Progression through GPCR/PI3K/AKT Pathway Inhibition

Despite advances in hepatocellular carcinoma (HCC) treatment, the discovery of novel bioactive molecules with well-defined mechanisms remains a critical need. This study identifies the branched-chain fatty acid iso15:0 as a potent suppressor of HCC progression and delineates its underlying molecular pathway. We demonstrated that iso15:0 significantly inhibits the proliferation and migration of HCC cells in vitro and suppresses tumor growth and metastasis in vivo. Transcriptomic profiling of treated cells revealed widespread alterations in gene expression, with Gene Set Enrichment Analysis (GSEA) pinpointing a significant suppression of the GPCR signaling pathway. Subsequent mechanistic investigations established that iso15:0 executes its function by specifically targeting the Gβγ subunits of heterotrimeric G proteins, thereby disrupting the downstream activation of the PI3K/AKT signaling cascade. This inhibition leads to cell cycle arrest and suppression of epithelial-mesenchymal transition (EMT). Our findings unveil a previously unrecognized tumor-suppressive function of iso15:0 and define a novel mechanism by which it inhibits HCC progression through targeted interference with the Gβγ–PI3K/AKT signaling axis. This work not only provides a mechanistic basis for the anti-tumor activity of iso15:0 but also highlights its potential as a promising lead compound for the development of new molecularly-targeted therapies against HCC.