6-Gingerol, an active compound of ginger, attenuates NASH-HCC progression by reprogramming tumor-associated macrophage via the NOX2/Src/MAPK signaling pathway.

Background: Non-alcoholic steatohepatitis-associated hepatocellular carcinoma (NASH-HCC) accounts for an increasing proportion of HCC cases. Currently, effective pharmacological options for treating both NASH and NASH-HCC remain limited, necessitating the identification of novel therapeutic agents. Our previous studies have demonstrated that ginger can ameliorate nonalcoholic fatty liver disease (NAFLD) and prevent the occurrence of NASH. The therapeutic effects and underlying mechanisms of NASH-HCC, however, remain poorly understood.

Methods: Network pharmacology, bioinformatics, single-cell RNA sequencing analysis, and molecular docking were used to identify the main active compounds, targets, and possible mechanisms of ginger in treating NASH-HCC. The anti-tumor efficacy and underlying mechanisms of the selected compound in treating NASH-HCC were validated through in vitro experimentation.

Results: Network pharmacology, bioinformatics, and molecular docking have revealed that 6-gingerol is the main active compound of ginger in treating NASH-HCC. SRC can be an essential target gene for ginger attenuating NASH-HCC progression, while the mitogen-activated protein kinase (MAPK) signaling pathway and reactive oxygen species (ROS) play equally important roles. Single-cell RNA sequencing of the HCC patients shows that the key targets of ginger in treating NASH-HCC are distributed in tumor-associated macrophage (TAMs). It has been reported that NOX2-derived ROS in macrophages can activate Src and then regulate downstream MAPK signaling cascades. 6-Gingerol can inhibit the proliferation, migration and reduce lipid deposition of liver cancer cells in vitro. More importantly, it induces polarization TAMs to M1 and enhances proinflammatory function, which may be achieved via the NOX2/Src/MAPK signaling pathway.

Conclusion: This study proves that 6-gingerol, the primary active compound in ginger, plays a role in attenuating the progression of NASH-HCC by inhibiting the proliferation and migration of tumor cells, or reprogramming TAMs to the M1 phenotype via the NOX2/Src/MAPK signaling pathway and activating the TAM-mediated immune responses.