Wuhan Jiulong Pharmaceutical Co., Ltd.

Intrahepatic cholangiocarcinoma (ICC) cells preferentially utilize aerobic glycolysis to support their uncontrolled proliferation. This metabolic reprogramming leads to lactate accumulation in the tumor microenvironment, which promotes the polarization of tumor-associated macrophages (TAMs) toward a pro-tumor phenotype, thereby facilitating immune escape and malignant progression. Although celastrol exhibits inhibitory effects on ICC, its underlying mechanism of action remains unclear. This study aims to elucidate whether celastrol suppresses ICC progression by targeting glycolysis and its subsequent impact on TAM polarization. The anti-tumor effect of celastrol and its influence on TAM polarization were systematically investigated using in vitro co-culture models and in vivo animal experiments. We demonstrated that celastrol significantly inhibits ICC progression and restrains the pro-tumor polarization of TAMs. Mechanistically, celastrol suppressed glycolysis in ICC cells and reduced lactate accumulation and further influenced TAMs polarization and ICC proliferation. In conclusion, our findings demonstrate that celastrol suppresses ICC progression by dually targeting glycolysis in tumor cells and lactate-mediated TAM polarization, highlighting its potential as a multi-faceted therapeutic agent against ICC.