Psmd4, also known as Rpn10, is a subunit of the 19S proteasome unit and a major ubiquitin receptor of the 26S proteasome. It is involved in feeding target proteins into the catalytic machinery of the 26S proteasome, playing a crucial role in the ubiquitin-dependent proteolytic pathway, which is vital for cellular regulation including cell cycle, differentiation, and apoptosis [2,4,5].

In multiple cancers, Psmd4 has shown significant effects. In hepatocellular carcinoma (HCC), loss of Psmd4 in HCC cells suppressed tumor development in mouse xenograft models. Psmd4 is associated with Akt/GSK-3β/cyclooxygenase2 (COX2) pathway activation, inhibition of p53 promoter activity, and increased p53 degradation, promoting HCC tumor growth [1,5]. In multiple myeloma, inducible knockout or knockdown of Rpn10 (Psmd4) decreased MM cell viability both in vitro and in vivo by triggering polyubiquitinated protein accumulation, cell cycle arrest, and apoptosis [2]. In esophageal cancer, knockdown of Psmd4 induced cell apoptosis, cell cycle arrest, and enhanced endoplasmic reticulum stress response [3]. In epithelial ovarian cancer, down-regulation of Psmd4 increased the sensitivity to carboplatin by inhibiting the NF-κB pathway, attenuating autophagy, and enhancing intracellular ROS accumulation [6]. In chemoresistant colorectal cancer, Psmd4 activated by cytoplasmic localization of Nrf2 may be responsible for chemoresistance via the NF-κB/AKT/β-catenin/ZEB1 cascades [7].

In conclusion, Psmd4 is essential in the ubiquitin-proteasome pathway and significantly impacts various cellular processes. Through gene knockout or knockdown studies in different cancer models, it has been revealed that Psmd4 plays a promoting role in the development and progression of multiple cancers, making it a potential therapeutic target for these diseases.