The E3 ligase TRIM29 drives renal ischemia-reperfusion injury by targeting DUSP10 for proteasomal degradation.

Renal ischemia-reperfusion injury (RIRI) represents a leading cause of acute kidney injury (AKI), yet the molecular determinants governing stress-induced signaling remain incompletely understood. Here, we identify TRIM29, an E3 ubiquitin ligase significantly upregulated in human and murine AKI, as a pivotal regulator of ischemic kidney injury. Using integrative transcriptomic and proteomic profiling, we show that TRIM29 directly interacts with and ubiquitinates DUSP10, a MAPK-specific phosphatase that restrains JNK/p38 activity. TRIM29 catalyzes K48-linked ubiquitination of DUSP10 at lysine 231, promoting its proteasomal degradation. The consequent depletion of DUSP10 sustains MAPK activation, which subsequently amplifies NF-κB-mediated inflammation and tubular epithelial cell apoptosis. Conversely, genetic ablation of TRIM29 in mice confers marked protection against renal dysfunction, structural damage, and inflammatory infiltration. Mechanistically, the TRIM29-DUSP10-MAPK axis defines a complete stress-responsive cascade that links ischemic stress to maladaptive tubular injury. Our findings reveal a previously unrecognized ubiquitin-dependent pathway governing post-ischemic renal pathology and identify the TRIM29-DUSP10 interface as a promising therapeutic target for AKI. The TRIM29-DUSP10-MAPK signaling axis in renal ischemia-reperfusion injury. TRIM29 targets DUSP10 for K48-linked polyubiquitination at lysine 231, promoting its proteasomal degradation and thereby sustaining JNK/p38 MAPK activation to drive maladaptive injury.