Targeting p38γ synergistically enhances sorafenib-induced cytotoxicity in hepatocellular carcinoma.

Sorafenib (Sora) is a first-line treatment for patients with advanced hepatocellular carcinoma (HCC). It can significantly improve the survival rate of patients with advanced HCC, but it is prone to drug resistance during treatment, so the therapeutic effect is extremely limited. Here, we demonstrate that an elevated expression of protein kinase p38γ in hepatocellular carcinoma cells diminishes the tumor cells' sensitivity to Sora. Pirfenidone (PFD) can augment Sora's inhibitory effect on hepatocellular carcinoma by specifically targeting p38γ. Our study further uncovers that pirfenidone can synergistically boost the anti-hepatocellular carcinoma impact of Sora by impeding the autophagy heightened by p38γ. Taken together, our findings suggest that pirfenidone can work in concert with Sora to intensify its anti-tumor effect on hepatocellular carcinoma, thereby offering a novel therapeutic approach for Sora-mediated tumor treatment. PFD is an inhibitor of p38γ, which may affect the Beclin pathway by inhibiting the function of p38γ, thereby inhibiting the level of autophagy, and ultimately achieving the effect of sensitizing Sora. Created with BioRender.com Graphical Headlights Knockdown of p38γ sensitized the inhibitory effect of Sora on HCC cells; PFD synergistically enhances the anti-HCC effect of Sora by targeting p38γ; PFD sensitizes the anti-HCC effect of Sora by inhibiting autophagy. [ABSTRACT FROM AUTHOR]