Aurora A exacerbates antibiotic-resistant Staphylococcus aureus infection through ASC phosphorylation.

Excessive inflammasome activation is increasingly recognized as a critical driver of pathology during bacterial infections, yet the pathogen-derived mechanisms that trigger dysregulated inflammasome responses remain poorly defined. Here, we identify a previously unrecognized role for the serine/threonine kinase Aurora A in promoting inflammasome activation during Staphylococcus aureus infection. We demonstrate that S. aureus activates JNK-dependent signaling in macrophages, leading to the phosphorylation of Aurora A. Activated Aurora A directly phosphorylates ASC, the inflammasome adaptor, on serine residues, enhancing ASC oligomerization and facilitating robust caspase-1 activation through both NLRP3 and AIM2 inflammasomes. This phosphorylation event stabilizes ASC speck formation and amplifies downstream IL-1β production, thereby intensifying inflammatory responses. Importantly, pharmacological inhibition or genetic disruption of Aurora A markedly suppresses inflammasome activation in vitro and in vivo, significantly reduces bacterial burdens and improves survival in mice infected with antibiotic-resistant S. aureus. These findings reveal Aurora A as a key host regulator exploited by S. aureus to potentiate inflammasome-driven inflammation and highlight inflammasome inhibition as a potential therapeutic strategy that augments host defense independently of antibiotic resistance.