SLC15A4 is a proton-coupled amino acid transporter localized to endolysosomal membranes that mediates the transport of L-histidine, di- and tripeptides, and bacterial peptidoglycans across the lysosomal membrane 12. The transporter preferentially binds short peptides with basic residues at the first position and hydrophobic residues at the second position 3, with activity optimized in acidic lysosomal conditions. SLC15A4 plays a central role in innate immunity by enabling pattern recognition receptor signaling. It mediates transport of NOD1 and NOD2 ligands (tri-DAP and MDP respectively) across endolysosomal membranes, facilitating microbial pathogen detection 12. Beyond its transporter function, SLC15A4 independently recruits the adapter protein TASL to endolysosomes, which subsequently activates IRF5 downstream of TLR7, TLR8, and TLR9 43, driving type I interferon production 1. Structurally, SLC15A4 undergoes conformational changes from outward- to inward-facing states to accommodate TASL binding 5. SLC15A4 regulates macrophage M1 polarization and metabolic stress resilience by controlling pyruvate-dependent glycolysis and AMPK activation 6. Genetically, SLC15A4 is associated with systemic lupus erythematosus and colitis in both humans and mice 78. These properties establish SLC15A4 as a validated therapeutic target for autoimmune and autoinflammatory diseases 910.