STK39 promotes the evolution cascade of hepatocellular carcinoma by facilitating PKR/NF-κB-mediated macrophage inflammatory response.

'Liver injury-liver fibrosis/cirrhosis-liver cancer' is the key evolution pathway of hepatocellular carcinoma (HCC), chronic inflammation serving as a major driving force in this process. However, the regulatory mechanisms underlying this process require further clarification. Here, the carcinogen-induced liver injury, liver fibrosis, and HCC models were investigated in the wild-type and STK39-knockout mice. Mass spectrometry analysis and immunoprecipitation assays were used to identify the interaction factors of STK39. QPCR, ELISA, and immunofluorescence were applied for the expression of inflammatory factors. In this study, we report that STK39 is gradually upregulated during the evolution of HCC (liver injury-liver fibrosis-liver cancer). Consequently, overexpression of STK39 further encouraged the evolution of HCC by facilitating a macrophage inflammatory response, as demonstrated in carcinogen-induced liver injury, liver fibrosis, and HCC models. Pharmacological inhibition of STK39 significantly slows the progression of HCC; however, this effect was considerably diminished after macrophage clearance. Mechanistically, mass spectrometry analysis and immunoprecipitation assays identified that STK39 interacted with PKR and promoted the activation of the PKR/NF-κB axis. Which, in turn, enhanced the macrophage inflammatory response and accelerated the evolution of HCC. The inflammatory factor TNF-α further induces the expression of STK39, suggesting a positive feedback regulation process exists. More notably, STK39 inhibition improves the efficacy of sorafenib and anti-PD1 therapy. In conclusions, our study reveals that STK39 holds significant potential for the early diagnosis and treatment of HCC.