{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nREG3A is a secreted C‐type lectin that plays a fundamental role in innate immunity by directly targeting Gram‐positive bacteria. It binds to the peptidoglycan carbohydrate backbone on the bacterial cell wall—using a conserved binding motif—in a calcium‐independent manner, and, in some instances, forms membrane‐permeabilizing complexes to disrupt bacterial membranes. These antimicrobial actions help maintain homeostasis in the intestinal lumen and limit bacterial penetration of mucosal surfaces."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its direct antibacterial effects, REG3A exerts important functions in epithelial homeostasis and tissue repair. In the skin, for example, inflammatory signals—such as those mediated by IL‑17—upregulate REG3A expression in keratinocytes, which in turn modulates cell proliferation and inhibits terminal differentiation to promote wound re‑epithelialization and accelerate repair. This regulatory function helps to mitigate excessive inflammation while facilitating tissue regeneration."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "7"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nREG3A also functions as a potent regenerative factor in multiple organ systems. In the heart, its release from dedifferentiating cardiomyocytes aids macrophage recruitment and myocardial healing. In the liver, REG3A (and its human homolog HIP/PAP) acts as a paracrine cytokine by stimulating hepatocyte proliferation and protecting against apoptosis, thereby enhancing regeneration after injury. In the pancreas, altered REG3A signaling is implicated in both the repair response following injury and in neoplastic processes in inflammation‐associated pancreatic carcinogenesis. Moreover, REG3A influences intestinal barrier integrity by modulating the microbiota and local cytokine milieu, and its dysregulation has been linked to various malignancies—including colorectal and gastric cancers—where it regulates key proliferation and survival pathways."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "20"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nThe biological activity of REG3A is tightly regulated at several levels. Post‐translationally, an N‑terminal prosegment inhibits its antimicrobial activity until proteolytic cleavage activates the protein. In addition, emerging evidence shows that long noncoding RNAs can form triplex structures with the REG3A promoter to steer its transcription, while conformational dynamics and even amyloid‐like aggregation properties may further impact its function and stability. Such regulatory mechanisms—together with receptor interactions (for example, binding to EXTL3 on epithelial cells)—govern its downstream signaling in tissue repair and regeneration."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "21", "end_ref": "24"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nClinically, circulating REG3A has proven to be a valuable biomarker and a potential therapeutic target in a range of inflammatory and neoplastic diseases. Elevated serum levels correlate with the severity of gastrointestinal graft‑versus‑host disease and inflammatory bowel disorders, while its expression in tissue specimens from head and neck, gastric, colorectal, ovarian, and liver cancers underscores its dual role in tumor promotion and suppression. Because REG3A levels also associate with adverse outcomes in acute injury (such as stroke), monitoring its concentration may help stratify disease severity and inform therapeutic strategies that modulate its activity to restore tissue homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "25", "end_ref": "35"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Heather L Cash, Cecilia V Whitham, Cassie L Behrendt, et al. 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