Discovery of targeting USP10-mediated proline metabolism arrangement to inhibit hepatocellular carcinoma progression.

Metabolic dysregulation is closely related to hepatocellular carcinoma (HCC) progression. Aberrant proline metabolism plays crucial roles in HCC onset and development. However, the detailed molecular mechanisms of proline metabolism in HCC remain unclear. In this study, we reported that hydroxyproline, a metabolite of proline, is a key causal factor of HCC progression using Mendelian randomization analysis. An elevated level of hydroxyproline promotes HCC cell growth, migration, and invasion. Using a non-targeted metabolomics approach, we found that USP10 increases the amount of proline and hydroxyproline in HCC cells. We subsequently proved that USP10 stabilizes Yes-associated protein 1 (YAP1), enhancing YAP1/TEA domain transcription factor 4 (TEAD4)-mediated transcription of prolyl 4-hydroxylase subunit alpha 1 (P4HA1). This leads to increased expression of P4HA1, which alters the proline catabolic profile. In contrast, knocking down USP10 or suppressing its activity reduced the expression of P4HA1. Given the crucial roles of USP10 in HCC progression, we further validated ginkgolic acid, a hit compound that targets USP10, leading to potential anti-HCC efficacy in xenograft mouse models. Overall, our study provides novel insights into the role and potential molecular mechanisms of USP10 on proline metabolism in HCC for the first time, as well as offers a promising therapeutic strategy of targeting USP10 for HCC treatment.