CTH Promotes Liver Cancer Progression and Exploratory Evaluation Supports Enhanced Antitumor Activity of PPG Plus GPC3 CAR-T Cells.

Although hydrogen sulfide (H2S) is a key regulator in cancer biology, the mechanism by which the H2S-producing enzyme cystathionine-γ-lyase (CTH) functions in hepatocellular carcinoma (HCC) remains elusive. Using the slow-releasing H2S donor GYY4137, we observed enhanced migration and invasion in HuH7 and HepG2 cells. Subsequently, we observed consistent protumorigenic effects of CTH not only in vitro but also in subcutaneous and orthotopic mouse models. Here, our findings suggest that CTH-H2S sulfhydrates Rab7a, which may be associated with HCC progression. We further showed that CTH modulates the expression of autophagy-related proteins in liver tumor cells. In nude mouse subcutaneous xenograft experiments, compared with the vehicle group, the combination of DL-propargylglycine (PPG, CTH inhibitor) and GPC3 CAR-T exhibited better antitumor efficacy compared to PPG or CAR-T alone. Our findings suggest that CTH modulation was associated with altered Rab7a sulfhydration and autophagy and that combined PPG and GPC3 CAR-T therapy exerts better antitumor efficacy.