TRIM21 inhibition alleviates acute kidney injury by promoting INTS3-associated DNA damage repair.

Acute kidney injury (AKI) is a common and severe clinical complication with limited treatment options. TRIM21, an E3 ubiquitin ligase, was previously shown to be upregulated in ischemia/reperfusion (I/R)-induced AKI. This study further revealed its role in DNA damage repair. Here, we demonstrated that TRIM21 expression is elevated in human kidney biopsies, murine AKI models, and injured renal tubular epithelial cells (TECs), in parallel with increased DNA double-strand breaks (DSBs). TRIM21 knockout attenuated renal injury, improved renal function, and decreased TECs apoptosis. Mechanistically, TRIM21 was found to bind to INTS3 and facilitate its proteasomal degradation, suppressing DNA repair and promoting apoptosis. INTS3 overexpression alleviated cisplatin-induced DNA damage and apoptosis in TECs. Through virtual screening and activity evaluation, SB33-0223 was identified as a small-molecule inhibitor targeting the C-terminal PRYSPRY domain of the TRIM21 protein. By blocking the recruitment of antibody-bound substrates, SB33-0223 effectively prevents TRIM21-mediated ubiquitination and degradation of INTS3, thereby enhancing INTS3 stability and reducing DNA damage in vitro and in vivo. Our study discovered SB33-0223 as an inhibitor of TRIM21 for the first time, highlighting the TRIM21/INTS3 axis as a critical regulator of DNA repair in AKI, supporting SB33-0223 as a promising lead for targeted therapeutic intervention.