iNOS/NO-Induced autophagy primes PANoptosis as the central driver of streptococcal toxic shock-like syndrome in zoonotic Streptococcus suis infection.

Streptococcus suis is a major zoonotic pathogen that causes human fulminant meningitis and streptococcal toxic shock-like syndrome (STSLS), the latter being driven by dysregulated inflammatory responses and explosive cytokine storms. It remains unclear whether PANoptosis acts as a coordinated host-protective response or instead serves as a detrimental driver of cytokine storm during bacterial infection. Here, we identify autophagy as an upstream orchestrator of PANoptosis during zoonotic Streptococcus suis infection, redefining STSLS as a disease driven by an integrated PANoptosis cell-death programme rather than parallel activation of individual death pathways. Mechanistically, S. suis infection activates a metabolic iNOS/NO-Bcl-2-autophagy pathway which in turn establishes PANoptosis as the dominant driver of cytokine storm and host damage. CRISPR/Cas9-mediated iNOS knockout in vitro, together with inhibition of iNOS/NO using the selective inhibitor 1400 W, markedly suppresses autophagy-mediated PANoptosis, attenuates cytokine storms, and protects mice from lethal STSLS, thereby establishing PANoptosis as the central driver of host damage in the pathology of STSLS. In the atudy, we uncover autophagy as a previously unrecognized upstream regulator of PANoptosis and pinpoint an iNOS/NO-autophagy pathway as both a key point for PANoptosis and a rational target for host-directed therapy in STSLS.