摘要Chronic,unresolved inflammation correlates with persistent hepatic injury and fibrosis,ulti-mately progressing to hepatocellular carcinoma(HCC).Bisdemethoxycurcumin(BDMC)demonstrates therapeutic potential against HCC,yet its mechanism in preventing hepatic"in-flammation-carcinoma transformation"remains incompletely understood.In the current re-search,clinical HCC specimens underwent analysis using hematoxylin-eosin(H&E)staining and immunohistochemistry(IHC)to evaluate the expression of fibrosis markers,M2 macro-phage markers,and CXCL12.In vitro,transforming growth factor-β1(TGF-β1)-induced LX-2 cells and a co-culture system of LX-2,THP-1,and HCC cells were established.Cell functions underwent assessment through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium brom-ide(MTT),flow cytometry,and Transwell assays.Reverse transcription-quantitative poly-merase chain reaction(RT-qPCR),Western blotting and immunofluorescence evaluated the differential expression of molecules.The interaction between β-catenin/TCF4 and CXCL12 was examined using co-immunoprecipitation(Co-IP),dual luciferase,and chromatin immun-oprecipitation(ChIP)assays.A DEN-induced rat model was developed to investigate BDMC's role in liver fibrosis-associated HCC(LFAHCC)development in vivo.Our results showed that clinical HCC tissues exhibited elevated fibrosis and enriched M2 macrophages.BDMC delayed liver fibrosis progression to HCC in vivo.BDMC inhibited the inflammatory microenvironment induced by activated hepatic stellate cells(HSCs).Furthermore,BDMC suppressed M2 macro-phage-induced fibrosis and HCC cell proliferation and metastasis.Mechanistically,BDMC repressed TCF4/β-catenin complex formation,thereby reducing CXCL12 transcription in LX-2 cells.Moreover,CXCL12 overexpression reversed BDMC's inhibitory effect on macrophage M2 polarization and its mediation of fibrosis,as well as HCC proliferation and metastasis.BDMC significantly suppressed LFAHCC development through CXCL12 in rats.In conclusion,BDMC inhibited LFAHCC progression by reducing M2 macrophage polarization through suppressingβ-catenin/TCF4-mediated CXCL12 transcription.