Degradation of NLRP3 by selective ROCK2 inhibitor alleviates acute lung injury

Acute lung injury (ALI), characterized by uncontrolled inflammatory responses, is a critical condition with limited clinical treatment options. Activation of the NLRP3 inflammasome represents a pivotal event in ALI pathogenesis. Although targeting NLRP3 (The NOD-like receptor (NLR) family member containing a pyrin domain 3) inflammasome has been considered to be a potential therapy, the underlying mechanism through which pathway the pulmonary inflammation is modulated remains controversial. Here, we demonstrate that 475A, a highly selective ROCK2 (Rho-associated coiled-coil forming protein kinases 2) inhibitor, effectively attenuates pulmonary inflammation and alleviates lung injury. Mechanistically, 475A promotes NLRP3 protein ubiquitination and subsequent proteasomal degradation by disrupting YAP (Yes-associated protein)-NLRP3 protein interactions, thereby suppressing inflammatory cytokine production in macrophages. This study provides the first evidence linking ROCK2 inhibition to enhanced NLRP3 degradation in ALI treatment, paving the way for developing 475A as a therapeutic agent and establishing the ROCK2/YAP/NLRP3 axis as a novel strategy for treating NLRP3-driven inflammatory diseases.