<p>XXX.</p>

Sphingomyelin phosphodiesterase (Sph) has emerged as a key virulence determinant of <i>S. aureus</i>; however, its potential role and underlying mechanisms in mastitis remain elusive.

In this study, we demonstrate that Sph deficiency significantly suppresses <i>S. aureus</i>-induced ferroptosis. Mechanistically, Sph disrupts mitochondrial cristae through interaction with Mic60, a core component of the mitochondrial contact site and cristae-organizing system (MICOS). Sph-mediated cytosolic mitochondrial DNA (mtDNA) released is sensed by cyclic GMP-AMP synthase (cGAS), leading to activation of the STING signaling pathway, which further triggers the recruitment of GPX4 into the autophagy-lysosome pathway for degradation.