The Hippo pathway kinase MST1 mediates a feedback loop to maintain NLRP3 inflammasome homeostasis.

Inflammasomes play pivotal roles in inflammatory responses. However, their activity must be tightly controlled to prevent overactivation and subsequent inflammatory diseases. Negative feedback loops represent a general mechanism to maintain signaling homeostasis, yet the mechanisms by which inflammasomes employ this process to prevent overactivation remain poorly understood. Here, we identify a negative feedback loop mediated by the Hippo pathway kinase mammalian Ste20-like kinase 1 (MST1) that prevents hyperactivation of the NLRP3 inflammasome. Mechanistically, NLRP3 inflammasome activation induces caspase-1-dependent cleavage of MST1 on its inhibitory linker region, resulting in enhanced kinase activity. The enhanced MST1 phosphorylates the inflammasome adaptor protein ASC at serine 58, disrupting ASC oligomerization and thereby attenuating inflammasome assembly. Notably, staurosporine (STS), a chemical inducer of MST1 cleavage, mitigates inflammation and tissue damage in a lipopolysaccharide (LPS)-induced sepsis mouse model. These findings reveal a negative feedback mechanism for maintaining inflammatory homeostasis and highlight MST1 cleavage as a potential therapeutic target for controlling inflammation.