{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSLC15A4 has emerged as a critical gene in the context of immune‐mediated diseases. Genome‐wide association studies in diverse populations have identified SLC15A4 as a susceptibility locus for systemic lupus erythematosus (SLE) and other complex disorders. Variants in SLC15A4 have been linked not only to SLE subphenotypes—such as the discoid rash observed in patients—but also to broader immune‐related conditions including type 2 diabetes and familial colorectal cancer, underscoring its importance in immune regulation and disease pathogenesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, SLC15A4, also known as PHT1, is an endolysosomal proton‐coupled transporter responsible for mediating the translocation of histidine and di/tripeptides from endolysosomes into the cytosol. Functional and structural studies have established that SLC15A4 plays an essential role in the innate immune response by facilitating endolysosomal Toll-like receptor (TLR7/8/9) signaling. Through its interaction with the immune adaptor protein TASL, SLC15A4 enables the recruitment and activation of IRF5, which in turn triggers type I interferon production. Its transport activity, regulated by parameters such as pH and temperature, is also intimately linked with the maintenance of mTORC1 signaling, autophagy sustainability, and mitochondrial integrity—critical processes for proper immune cell function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGiven its central role in linking pathogen recognition to downstream inflammatory signaling, SLC15A4 represents a promising therapeutic target for autoimmune and inflammatory diseases. Recent pharmacological strategies—such as those using molecules like feeblin—demonstrate that disrupting the SLC15A4–TASL interaction effectively impairs TLR7/8-driven IRF5 activation and proinflammatory cytokine production. Further, the overexpression of SLC15A4 in inflamed epithelial tissues, such as those found in ulcerative colitis, reinforces its contribution to disease pathology. Coupled with insights from recent reviews on its broader functions in lysosomal homeostasis and immune regulation, these findings pave the way for novel structure-guided drug development efforts."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jian-Wen Han, Hou-Feng Zheng, Yong Cui, et al. 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