Discovery of a Covalent NLRP3 LRR-Domain Probe: Reversing Renal Fibrosis via Immunometabolic Reprogramming in Organoid and Murine Models

This is the authors' abstract. We don't add key points for this paper.

Targeting the NLRP3 inflammasome is critical for treating fibrotic diseases; however, current NACHT domain inhibitors face mutational escape and limited isoform specificity. The autoinhibitory leucine-rich repeat (LRR) domain represents an underexplored pharmacological target. Here, we report QX-31, a novel covalent probe selectively engaging the LRR domain. QX-31 covalently binds to Cysteine 838, stabilizing NLRP3 in an inactive conformation and preventing inflammasome assembly with high selectivity over AIM2 and NLRC4. Furthermore, QX-31 reverses maladaptive immunometabolic reprogramming within the renal microenvironment by blunting the PI3K/AKT/HIF-1α axis, suppressing aberrant glycolysis and glutaminolysis. Evaluated in human kidney organoids and murine models of renal injury (UUO and IRI), QX-31 demonstrated potent antifibrotic efficacy comparable to reference drugs, alongside a favorable safety profile. Collectively, QX-31 serves as a valuable chemical tool, demonstrating that covalent targeting of this conformational regulatory domain is a viable therapeutic strategy for fibrotic diseases.