{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSPRR3 is a small proline‐rich protein that serves as a crucial cross‐bridging component of the cornified cell envelope, thereby contributing to epithelial barrier formation and terminal differentiation. Its proper expression is essential for maintaining skin homeostasis, as genetic variants in SPRR3 have been linked to inflammatory skin conditions such as eczema and psoriasis. In normal epithelia, SPRR3 (also known as esophagin) displays a distinct distribution in differentiated cell layers and is altered in conditions such as human papillomavirus infection of the genital epithelium. Moreover, both genetic association studies and transcriptional analyses have implicated abnormal SPRR3 expression in inflammatory skin disorders, with altered levels correlating with disease severity in atopic dermatitis. Environmental stressors, such as exposure to fine particulate matter (PM2.5), can upregulate SPRR3 via c-Jun activation, which in turn impairs primary cilium formation in keratinocytes."}, {"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": "\nIn the context of tumorigenesis, SPRR3 exerts context‐dependent functions. In esophageal squamous cell carcinoma, its downregulation has been observed as an early event during malignant transformation, and experimental restoration can promote apoptosis via upregulation of pro‐apoptotic mediators. Conversely, SPRR3 is overexpressed in several solid tumors—including colorectal, breast, and pancreatic cancers—where its upregulation enhances cell proliferation, invasion, and tumor aggressiveness through activation of signaling pathways such as AKT, MEK/MAPK, and NF‑κB, often accompanied by p53 downregulation. Moreover, distinct mRNA splice variants of SPRR3 in esophageal tissues and its association with increased sensitivity to DNA damage via mitochondrial pathways further underscore its potential as a diagnostic and prognostic biomarker in cancer."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in epithelial integrity and tumor progression, SPRR3 functions as a mechanosensitive protein in non‐epithelial cells. In vascular smooth muscle cells, mechanical cyclic strain induces SPRR3 expression via integrin α1β1 interactions, suggesting its involvement in cellular adaptation to biomechanical stress within atherosclerotic plaques. In parallel, studies in allergic airway inflammation have demonstrated that reducing SPRR3 levels diminishes eosinophilic infiltration and type 2 cytokine production by modulating IL‑33 and PI3K/AKT/NF‑κB signaling. In addition, the detection of distinct SPRR3 isoforms in bodily fluids, such as saliva from preterm newborns, hints at broader systemic roles that merit further investigation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Elizabeth Lehr, Daniel Hohl, Marcel Huber, et al. 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