DeLeon-Pennell KY, et al. - Whether sex differences in cardiac remodeling in mice and humans could be explained by differential signaling activation following myocardial infarction (MI) was investigated by assessing sex differences in post-MI responses using a combination of experimental MI in mice and human post-MI proteomic data from the Jackson Heart Study. In female mice, desensitization to liver X receptors/retinoid X receptor (LXR/RXR) signaling was observed with age, which caused enhanced interleukin-6 activation. This finding was reproduced in the JHS community cohort. For the first time, sex differences in post-MI neutrophil signaling were uncovered via this investigation, demonstrating better outcomes in young females and worse outcomes with age. The occurrence of inflammation resolution, which represented a critical component of MI remodeling, was observed under sex-dependent mechanisms.