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

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.

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.

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.

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.