GPx4 is an enzyme that reduces oxidized phospholipids in a glutathione-dependent manner. GPx4 is also a regulator of lipid oxidation-dependent cell death ferroptosis (iron-dependent) and lipoxytosis (iron-independent), which have recently attracted much attention. Mice deficient in cardiac-specific GPx4 are lethal during development, but grow normally when fed a vitamin E-supplemented diet. Conversely, when heart-specific GPx4-deficient mice that have grown normally are switched from a vitamin E-supplemented diet to a normal diet, sudden cardiac death is induced in about 15 days by increase of lipid peroxidation in heart. Using these mice as a model of lipid oxidation-dependent heart failure, we screened for drugs and food ingredients that can suppress heart failure. As a result, we found several heart failure inhibitors with lipid oxidation inhibitory activity. Surprisingly, however, we also found that food ingredients and antibiotics without lipid oxidation inhibitory activity could suppress lethality. Analysis of the mechanism revealed that these antibiotics inhibit cardiac lipid oxidation by altering the intestinal microbiota. It was also found that administration of this intestinal bacterium also suppressed lipid oxidation-dependent heart failure. This finding opens the way for the development of new therapeutic agents for heart failure.