PFDN6L Gene Predicts Good Prognosis Associated with Its Inhibition of the Stem-Ness Properties in Hepatocellular Carcinoma.

BACKGROUND: Liver cancer stem cells (LCSCs) are recognized as pivotal drivers of hepatocellular carcinoma (HCC) progression; however, the molecular mechanisms maintaining their stem-like phenotype remain largely unresolved. This work investigates the role of prefoldin subunit 6-like protein (PFDN6L) in shaping LCSC traits and promoting or restraining HCC progression. METHODS: PFDN6L, a cytoskeleton-associated chaperone, was studied using multiple in vitro assays-cell growth evaluation, cell cycle profiling, and spheroid culture-alongside analyses of stemness-associated markers (SOX2, CD133, CD44). Tumorigenic capacity was assessed in xenograft mouse models, and signaling pathway interrogation was performed to define underlying mechanisms. RESULTS: In patient samples, higher PFDN6L expression correlated with improved survival outcomes. Forced expression of PFDN6L induced G2/M arrest, diminished sphere formation, and reduced pluripotency marker expression, whereas knockdown accelerated in vivo tumor formation. Mechanistic experiments demonstrated that PFDN6L suppresses malignancy by simultaneously dampening AKT and ERK1/2 activation, thereby impairing oncogenic signaling cascades. CONCLUSION: PFDN6L acts as a negative regulator of LCSC-driven tumorigenesis. Its dual blockade of AKT and ERK pathways forms the mechanistic basis of its tumor-suppressive action, supporting its potential as a prognostic biomarker and therapeutic target in HCC.