NLRP3 inflammasome in acute kidney injury: molecular mechanisms, post-translational regulation, and immunotherapeutic potential.

Acute kidney injury (AKI) is a critical clinical syndrome characterized by a rapid decline in renal function. Dysregulated inflammatory responses play a crucial role in its pathogenesis, contributing to high patient mortality and a tendency to progress to chronic kidney disease (CKD). As a crucial sensor of the innate immune system, the NLRP3 inflammasome participates in the occurrence and development of AKI and its transition to CKD by activating caspase-1, promoting the maturation of IL-1β/IL-18, and inducing pyroptosis. This review elucidates the molecular composition of the NLRP3 inflammasome, its canonical and non-canonical activation pathways, and, for the first time, integrates the critical roles of post-translational modifications-including ubiquitination, phosphorylation, acetylation, SUMOylation, and palmitoylation-in regulating its activation, as well as their specific activation mechanisms across distinct subtypes of AKI. The specific mechanisms and pathological significance of the NLRP3 inflammasome in ischemia-reperfusion, sepsis-associated, and contrast-induced AKI were analyzed. Furthermore, we summarize current interventional strategies targeting the NLRP3 inflammasome and its upstream/downstream molecules, including direct inhibitors, mitophagy inducers, K+ channel modulators, caspase-1 inhibitors, and indirect inhibitor-based agents. Moreover, we assess their protective effects in AKI animal models and the bottlenecks in clinical translation. Finally, future research directions are proposed, such as cell type-specific functional analysis, dynamic regulation of post-translational modifications, and combined targeted therapy for the long-term transition of AKI to CKD, aiming to provide a theoretical basis and novel ideas for the precise therapy of AKI.