USP44 Regulates Chemoresistance Induced by ROS and the MAPK/NF-κB Pathway Through the Stabilization of ITGB4 in Gastric Cancer

Cisplatin (DDP) is a typical chemotherapy agent employed in gastric Cancer (GC). Resistance development significantly impairs the success of GC therapy, and the essential mechanisms are not yet fully understood. Deubiquitinase enzymes are pivotal in mediating drug resistance across various cancers via ubiquitin-mediated protein degradation. USP44, a Deubiquitinase known as Ubiquitin-Specific Peptidase 44, is implicated in the development of tumors, their spread, and resistance to treatment, although its specific role in gastric Cancer has yet to be clarified. We found a significant upregulation of USP44 expression in GC tissues compared to normal tissues, and it serves as a potential indicator of chemotherapy response and survival in GC. Through proteomic analysis, ITGB4 was recognized as a new substrate of USP44. Mechanistically, USP44 stabilizes ITGB4 via deubiquitination, thereby mitigating cisplatin resistance in GC cells by modulating ROS and the MAPK/NF-κB pathway. In addition, ITGB4 affects the expression of P-gp and the activity of antioxidant Enzymes through the MAPK/NF-κB pathway, thereby promoting cisplatin efflux and chemoresistance. Our research uncovers a novel mechanism behind cisplatin resistance and indicates that USP44 could be a promising therapeutic target for overcoming cisplatin resistance in gastric Cancer patients.

ITGB4; MAPK/NF‐κB signaling pathway; USP44; chemoresistance; gastric cancer; ubiquitylation.