SLC15A4 is a proton-coupled amino-acid transporter localized to endolysosomal membranes that plays a central role in innate immunity. The transporter mediates pH-dependent transport of L-histidine and di- and tripeptides from the lysosomal lumen to the cytosol, with substrate specificity favoring peptides containing a basic residue at the N-terminus and hydrophobic residue at position two 1. Beyond its transporter function, SLC15A4 serves as a critical platform for immune signaling: it recruits the adapter protein TASL to endolysosomes downstream of TLR7, TLR8, and TLR9 activation, enabling IRF5 recruitment and type I interferon production 2. This adaptor role is independent of SLC15A4's transporter activity. The transporter also mediates bacterial peptidoglycan uptake, including muramyl dipeptide (NOD2 ligand) and tri-DAP (NOD1 ligand), linking pathogen sensing to innate immune activation 3. SLC15A4 regulates mTORC1 signaling and macrophage metabolic remodeling toward the pro-inflammatory M1 phenotype 4. Genetic variants in SLC15A4 are associated with systemic lupus erythematosus in humans, and SLC15A4-deficient mice show ameliorated disease in lupus and colitis models. Recent chemical-proteomics studies have identified SLC15A4 inhibitors, including feeblin, which suppress TLR and NOD signaling and demonstrate anti-inflammatory activity in immune cells from lupus patients 5, establishing SLC15A4 as a druggable therapeutic target for autoimmune conditions.