GTP-binding proteins (G proteins) are key intracellular signal mediators in response to extracellular physicochemical stimuli. The C-terminus of G proteins is a hypervariable region whose living structure is difficult to unravel, and we found that cysteine in this region has high redox activity and is involved in stress response and adaptation in the heart. We also revealed that the cysteine has a multiple sulfur atom-linked (supersulfide) residue (Cys -S_(n)SH, n≥1), which negatively regulates the functional activity of G proteins. Not only protein-bound supersulfides, but also intracellular inorganic supersulfides are highly nucleophilic and react positively with electrophilic lipid peroxides, which may act as an anti-oxidant and anti-cytotoxic agent. Furthermore, desupersulfidation of the mitochondria fission-accelerating G protein, dynamin-related protein 1, has been shown to promote the accumulation of lipid droplets in the liver due to high fat loading. In this symposium, we will also address the potential of sulfur-based lipid-redox interactions as a new therapeutic target.