Targeting STAT3 with Conditional Knockout or PROTAC Technology Alleviates Renal Injury by Limiting Pyroptosis [RNA-seq]

The role of signal transducer and activator of transcription protein 3 (STAT3) in AKI remains controversial. Our study demonstrated an upregulation of total STAT3 protein in AKI mouse models induced by cecal ligation and puncture (CLP) or ischemia-reperfusion (I/R), correlating with patient biopsy results. This increase may be attributed to histone H3K27 acetylation. STAT3 knockout in renal tubular epithelial cells significantly reduced AKI injury and inflammation in mice. Mechanistically, STAT3 induces the transcription of tripartite motif-containing protein 21 (TRIM21), triggering a cascade that activates gasdermin D (GSDMD), resulting in pyroptosis. Administration of the novel proteolysis-targeting chimera (PROTAC) compound E034, which selectively targets STAT3 for ubiquitination and degradation, significantly alleviated renal injury in a low-dose, single-dose regimen, underscoring its substantial therapeutic potential with infrequent dosing requirements. In the context of renal injury, PROTAC emerges as a promising modality by specifically targeting the STAT3/TRIM21/GSDMD axis, which our study has identified as a potential therapeutic target, thereby potentially endowing novel and clinically significant therapeutic strategies.