Nuclear envelope rupture and DNA damage driven by high pressure are mediated by F-actin and induce hepatocyte inflammation via cGAS-STING.

Alterations in physical traits of the microenvironment contribute to the progression and malignancy of hepatocellular carcinoma (HCC). As liver inflammation gives rise to the initiation and progression of HCC, it remains largely unknown how mechanical cues induce inflammation in the HCC microenvironment and its pathological relevance to HCC progression. In this study, pressure of 5 mmHg and 40 mmHg were used to simulate the condition of normal liver tissue and HCC tumor. It was found that high pressure (40 mmHg) induced inflammation in THLE-3 hepatocytes. High pressure activated the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING), a DNA-sensing and inflammatory signaling pathway, and the inhibition of STING ameliorated the high-pressure-induced hepatocyte inflammation, suggesting that high pressure induces hepatocyte inflammation via activating cGAS-STING pathway. Mechanistically, high pressure induced DNA damage, severe nuclear deformation, and NE rupture in hepatocytes and resulted in cytoplasmic DNA leakage via F-actin-polymerization-mediated mechanotransduction. F-actin inhibition attenuated the pressure-activated cGAS-STING pathway and hepatocyte inflammation. Further, conditioned medium from high-pressure-treated hepatocytes facilitated the polarization of M2 macrophages, a pro-tumor phenotype, which could be deprived by blocking F-actin polymerization. Together, our study demonstrated a novel mechanism that high pressure in the HCC microenvironment drives hepatocyte inflammation by inducing NE rupture and DNA damage via polymerizing F-actin, and subsequently activates cGAS-STING signaling pathway, which favors polarization of macrophages to a pro-tumor phenotype (M2). Our study provides a prospect of mechanotherapy for HCC and liver inflammation by pharmacological blockage of mechanotransduction.