Slc15a3, also known as PHT2, is a proton-coupled oligopeptide/histidine transporter. It is mainly expressed on the lysosomal membrane of macrophages, and is involved in innate immune and antiviral signaling pathways, as well as the regulation of inflammatory responses [1,4,5]. It participates in transporting histidine, certain dipeptide and peptidomimetics from inside the lysosome to cytosol, and plays a role in maintaining metabolic and endolysosomal homeostasis [3,5,6].

In gene-knockout related studies, deficiency of Slc15a3 protected mice from pulmonary fibrosis. It resisted oxidative stress in macrophages, regulated the p62-NRF2 antioxidant stress pathway related to reactive oxygen species production, and maintained the homeostasis of the pulmonary microenvironment [1]. In ischemic stroke mouse models, inhibition of Slc15a3 reduced infarct area, attenuated neurological deficit, and mitigated apoptotic neurons by suppressing M1-type microglia polarization [2].

In conclusion, Slc15a3 is crucial for regulating macrophage-related functions such as oxidative stress and inflammatory responses. Gene-knockout mouse models have revealed its significant roles in diseases like pulmonary fibrosis and ischemic stroke, providing potential therapeutic targets for these conditions.