Slc15a3, also known as the oligopeptide/histidine transporter PHT2, is a proton-coupled histidine and di-tripeptide transporter located mainly on the lysosomal membrane of macrophages. It is involved in innate immune and antiviral signaling pathways, and plays a role in regulating endolysosomal functions, such as maintaining metabolic and endolysosomal homeostasis [3,4,5,6,7,8,9].

In gene-knockout (KO) mouse models, deficiency of Slc15a3 protected mice from pulmonary fibrosis induced by bleomycin or radiation. It resisted oxidative stress in macrophages by interacting with the scaffold protein p62, regulating its expression and phosphorylation activation, thus influencing the p62-NRF2 antioxidant stress pathway related to reactive oxygen species (ROS) production [1]. In ischemic stroke models, inhibition of Slc15a3 reduced infarct area, attenuated neurological deficit, and mitigated apoptotic neurons by suppressing microglia polarizing towards M1 subtypes [2].

In conclusion, Slc15a3 is crucial for innate immune responses, antiviral defenses, and the regulation of endolysosomal functions. KO mouse models have revealed its significance in pulmonary fibrosis and ischemic stroke, highlighting its potential as a therapeutic target for these diseases.