Overexpression of NK4 suppresses hepatocellular carcinoma progression by inducing apoptosis and autophagy via MAPK pathway inhibition

Hepatocellular carcinoma (HCC) remains a therapeutic challenge, necessitating novel treatment strategies. This study explored the antitumor activity and underlying mechanisms of NK4 overexpression in HCC. Utilizing engineered NK4-overexpressing HepG2 cells and a TPA-inducible TP-NK4 system evaluated in both HepG2 and MHCC97-H cells, we demonstrated that NK4 significantly inhibits HCC cell proliferation and migration in vitro. Furthermore, NK4 potently induced apoptotic cell death, as evidenced by the modulation of key regulators Bax and Bcl-2. Crucially, the induction of NK4 expression also promoted Autophagy and attenuated tumor growth in a mouse xenograft model. Mechanistic analysis indicated that inhibition of the MAPK pathway is central to these Anticancer effects. Our integrated findings establish NK4 as a potent multi-faceted inhibitor of HCC progression and highlight its strong therapeutic potential for precision oncology applications by targeting Apoptosis, Autophagy, and MAPK signaling.