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 p38 gamma 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 p38 gamma. Our study further uncovers that pirfenidone can synergistically boost the anti-hepatocellular carcinoma impact of Sora by impeding the autophagy heightened by p38 gamma. 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.