MAGED4 promotes hepatocellular carcinoma progression via activation of JAK2/STAT3 pathway by stabilizing TRIM21.

Melanoma-associated antigen D4 (MAGED4) belongs to the melanoma-associated antigen family and is upregulated in various cancer types. However, the functional role and molecular mechanisms of MAGED4 in hepatocellular carcinoma (HCC) remain largely unknown. In this study, we observed that MAGED4 expression levels were significantly higher in HCC tissues than in non-cancerous tissues and elevated expression was associated with poor patient outcomes. Functional assays demonstrated that MAGED4 promoted proliferation and migration of HCC. We found that MAGED4 can activate the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway. Mass spectrometry and co-immunoprecipitation assays revealed an interaction between MAGED4 and tripartite motif-containing 21 (TRIM21). Confocal microscopy experiments confirmed the colocalization of MAGED4 with TRIM21. Mechanistically, MAGED4 can regulate the stability of TRIM21 by preventing its ubiquitination and degradation. Furthermore, MAGED4 contributes to the downregulation of suppressor of cytokine signaling 3 (SOCS3) via TRIM21, and this effect can be partially reversed by si-TRIM21 in MAGED4-overexpressing cells. These findings indicate that MAGED4 promotes HCC progression through the activation of the JAK2/STAT3 pathway by stabilizing TRIM21, suggesting that targeting MAGED4 may provide new insights into HCC treatment strategies.