Q11, a CYP2E1 inhibitor, exerts anti-hepatocellular carcinoma effect by inhibiting M2 macrophage polarization

Despite significant advancements in cancer immunotherapy, many patients continue to respond poorly. Novel therapeutic strategies and drugs are urgently needed. Here, we found that CYP2E1 is significantly upregulated in M2 macrophages. The CYP2E1 inhibitor, Q11, could inhibit M2 macrophage polarization, while CYP2E1 overexpression could promote it. Increased levels of CYP2E1 and M2 macrophages in the tumor microenvironment of HCC patients correlate with poor prognosis. Q11 could inhibit tumor cells by targeting M2 macrophages rather than directly attacking tumor cells. Both Q11 and Cyp2e1 knockout could effectively suppress tumor growth. Q11 reduces the production of CYP2E1 metabolites (±)9(10)-DiHOME and (±)12(13)-DiHOME, thus attenuating PPAR? activation and M2 macrophage polarization. In summary, our findings suggest that Q11 could suppress M2 macrophage polarization by modulating the CYP2E1/(±)9(10)-DiHOME or (±)12(13)-DiHOME/PPAR? axis, indicating that CYP2E1 inhibition may be a novel therapeutic strategy for HCC and positioning Q11 as a promising therapeutic agent. Overall design: The experiment was divided into three groups: control group, model group, and drug treatment group. J774A.1 cells were used. Cells in the control group were cultured under normal conditions. Cells in the model group were induced into M2 macrophages by treatment with 10 ng/mL IL-4 and IL-13, respectively. In the Q11 group, Q11 was added simultaneously with IL-4 and IL-13 during the induction process.