TRIM47 drives metabolic reprogramming and tumor progression in Nasopharyngeal Carcinoma via K48-linked ubiquitination and degradation of SDHB.

Nasopharyngeal carcinoma (NPC) remains a therapeutically challenging malignancy due to its late diagnosis and limited treatment efficacy. Although metabolic reprogramming is a hallmark of cancer, the ubiquitin-mediated mechanisms underlying NPC progression are incompletely understood. Here, we demonstrate that tripartite motif-containing protein 47 (TRIM47) is significantly upregulated in NPC tissues and drives tumor aggressiveness. Through integrated in vitro and in vivo approaches, we found that TRIM47 promotes proliferation, migration, epithelial-mesenchymal transition (EMT), and tumor growth. Mechanistically, TRIM47 directly interacts with succinate dehydrogenase subunit B (SDHB)-a key component of mitochondrial complex II-via its B30.2/SPRY domain and catalyzes K48-linked polyubiquitination, leading to SDHB proteasomal degradation. This degradation induces metabolic reprogramming characterized by enhanced aerobic glycolysis, as evidenced by increased glucose consumption and lactate production. Critically, the oncogenic effects of TRIM47 were reversed by SDHB reconstitution. Moreover, supplementation with succinate, the enzymatic product of SDH, counteracted the tumor-suppressive effects of TRIM47 knockdown. Furthermore, exploiting the metabolic vulnerability induced by TRIM47, ascorbate treatment effectively suppressed TRIM47-driven tumor growth. Our results identify TRIM47 as a novel E3 ligase responsible for SDHB ubiquitination and degradation, thereby promoting Warburg-like metabolism and NPC progression. These findings unveil the TRIM47-SDHB axis as a promising therapeutic target and support metabolic intervention with ascorbate as a potential precision strategy for NPC treatment.