TRIM21‐Mediated K11‐Linked Ubiquitination of ID1 Suppresses Tumorigenesis and Promotes Cuproptosis in Esophageal Squamous Cell Carcinoma

Abstract Inhibitor of DNA binding 1 (ID1) is a key transcriptional regulator involved in the development of various cancers, including esophageal squamous cell carcinoma (ESCC). However, the mechanisms regulating ID1 ubiquitination in ESCC are not well understood. This study identifies TRIM21 as a novel E3 ubiquitin ligase that targets ID1 for K11‐linked ubiquitination at lysine 91. Unlike typical ubiquitination that marks proteins for degradation, TRIM21‐mediated K11 ubiquitination does not affect ID1 stability. Instead, it disrupts the ID1‐TCF12 interaction, releasing TCF12 to activate SLC31A1, a copper transporter. Elevated SLC31A1 expression increases intracellular copper, inducing cuproptosis and inhibiting ESCC cell proliferation and tumor growth. Functional assays show that overexpressing TRIM21 suppresses ESCC progression, while TRIM21 knockdown promotes growth. Clinically, low TRIM21 expression correlates with advanced disease stage and poorer patient survival rate, underscoring its prognostic value. Additionally, Sorafenib treatment upregulates TRIM21, enhancing ID1 ubiquitination, increasing SLC31A1 expression, and inducing cuproptosis. These findings uncover the TRIM21‐ID1‐TCF12‐SLC31A1 axis as a critical pathway in ESCC progression, suggesting that targeting this axis with Sorafenib can offer a promising therapeutic strategy for inhibiting tumor growth and improving patient outcomes.