USP3L facilitates gastric cancer progression via the Hippo/YAP axis

Gastric cancer (GC) is a prevalent digestive system malignancy where hyperactivation of the YAP/TEAD transcriptional axis plays a critical role in tumor progression. While the Hippo pathway's dysregulation in GC is established, the mechanisms sustaining YAP activity remain incompletely understood. Here, we identify the deubiquitinase USP3L as a pivotal regulator of Hippo signaling in GC. Clinical cohort analysis reveals that USP3L is significantly upregulated in GC tissues and correlates with advanced TNM staging and lymph node metastasis. Functionally, both genetic depletion and pharmacological inhibition of USP3L markedly suppress GC cell proliferation, stemness, and tumor xenograft growth. Mechanistically, the C19 peptidase domain of USP3L interacts with the WW domain of YAP, effectively inhibiting its K48-linked polyubiquitination. This interaction preserves YAP protein stability and amplifies YAP/TEAD transcriptional output. Intriguingly, YAP, primarily via TEAD1, transcriptionally upregulates USP3L by binding directly to its promoter region, establishing a reciprocal activation circuit. Collectively, these findings uncover a positive feedback loop between USP3L and the Hippo/YAP axis in gastric tumorigenesis, highlighting USP3L as a promising therapeutic target for YAP-driven malignancies.