Mammals produce cyclo -octasulfur to suppress lipid peroxidation and ferroptosis

Elemental sulfur is an evolutionarily ancient metabolite, yet its generation, storage, and function in animals have remained unclear. We show that mammals harbor elemental sulfur in the form of its most stable allotrope, cyclo -octasulfur (S 8 ). We found that S 8 accumulates to millimolar concentrations in mitochondrial membranes and in lipid droplets in both mouse and human cells. We further identified lipid droplet–associated nitric oxide synthase as a source of S 8 biosynthesis and found that S 8 accumulation in lipid droplets limits lipid peroxidation and suppresses ferroptosis. Accordingly, intra-articular injection of solubilized S 8 reduces lipid peroxidation in a mouse model of osteoarthritis. Together, these findings reveal an endogenous pool of S 8 in mammals that may protect cells from oxidative membrane damage by modulating cellular sensitivity to ferroptosis.