Bisdemethoxycurcumin suppresses liver fibrosis-associated hepatocellular carcinoma via inhibiting CXCL12-induced macrophage polarization

Background: Chronic, unresolved inflammation is associated with persistent hepatic injury and fibrosis, ultimately leading to hepatocellular carcinoma (HCC). Bisdemethoxycurcumin (BDMC) has shown therapeutic effects on HCC, but its role in preventing hepatic "inflammation-carcinoma transformation" remains unclear. Methods: Clinical HCC specimens were analyzed using HE staining and immunohistochemistry (IHC) to detect the expression of fibrosis markers, M2 macrophage markers, and CXCL12. In vitro, TGF-β1-induced LX-2 cells and a co-culture system of LX-2, THP-1, and HCC cells were established. Cell functions were assessed separately using MTT, flow cytometry, and transwell assays. RT-qPCR, Western blotting and immunofluorescence assessed the differential expression of the molecules. The relationship between β-catenin/TCF4 and CXCL12 was investigated using Co-IP, dual luciferase, and ChIP assays. A DEN-induced rat model was created to investigate the role of BDMC in liver fibrosis-associated hepatocellular carcinoma (LFAHCC) development in vivo. Results: Elevated fibrosis and enriched M2 macrophages were observed in clinical HCC tissues. BDMC delayed the progression of liver fibrosis to HCC in vivo. BDMC inhibited inflammatory microenvironment induced by activated hepatic stellate cells (HSCs). Additionally, BDMC suppressed M2 macrophage-induced fibrosis, as well as HCC cell proliferation and metastasis. Mechanically, BDMC repressed the formation of TCF4/β-catenin complex, thereby decreasing CXCL12 transcription in LX-2 cells. Meanwhile, overexpression of CXCL12 reversed the inhibitory effect of BDMC on macrophage M2 polarization and its mediation of fibrosis, as well as HCC proliferation and metastasis. BDMC significantly inhibited the development of LFAHCC through CXCL12 in rats. Conclusion: BDMC inhibited LFAHCC progression by reducing M2 macrophage polarization through suppressing β-catenin/TCF4-mediated CXCL12 transcription.