{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nWnt inhibitory factor‐1 (WIF1) is a secreted antagonist of Wnt signaling that exerts its biological functions by binding directly to various Wnt ligands, thereby modulating both canonical (β‐catenin–dependent) and non‐canonical pathways. Structural and promoter analyses have revealed that WIF1 contains a highly conserved WIF domain with an unexpected phospholipid‐binding pocket, and its expression appears to be subject to negative feedback regulation by β‐catenin activity. These mechanistic insights underscore WIF1’s role as a gatekeeper in controlling Wnt‐mediated cellular responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "Disruption of WIF1 function is a recurrent event in a variety of malignancies. In several cancers—including osteosarcoma, cervical, bladder, pituitary, renal, glioblastoma, mesothelioma, and salivary gland tumors—loss or marked downregulation of WIF1 (often through promoter hypermethylation) has been associated with enhanced Wnt signaling. Experimental re‐expression of WIF1 in tumor cells leads to reduced β‐catenin levels, inhibited cell proliferation, induction of differentiation or cell cycle arrest, and diminished tumor growth and metastasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "19"}]}, {"type": "t", "text": "Epigenetic silencing via promoter hypermethylation is one of the key mechanisms leading to WIF1 downregulation in many tumors. Studies have demonstrated that treatment with DNA demethylating agents (such as 5‐aza‐2′‐deoxycytidine, procaine or natural compounds like adiponectin and isoliquiritigenin) can restore WIF1 expression, which in turn dampens aberrant Wnt/β‐catenin activity, decreases cancer stem cell properties, and enhances chemosensitivity and radiosensitivity. Such reactivation strategies support the concept that reversal of WIF1 silencing may be therapeutically exploited in cancers ranging from nasopharyngeal carcinoma to lung, breast, hepatocellular, and oral carcinomas."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "20", "end_ref": "30"}]}, {"type": "t", "text": "Beyond its well‐documented role in tumor suppression, WIF1 also influences nonmalignant processes. Altered WIF1 expression has been linked to skin homeostasis and pigmentation disorders—where reduced levels in keratinocytes and fibroblasts correlate with enhanced melanogenesis in conditions such as melasma and psoriasis—as well as to modulation of intracellular signaling pathways (including Akt and p38‐MAPK) that affect cancer cell invasiveness and stemness. These multifaceted functions indicate that WIF1 is a critical regulator not only of oncogenic cell signaling but also of the microenvironment and differentiation programs in both healthy and diseased tissues."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "31", "end_ref": "34"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Noemi Reguart, Biao He, Zhidong Xu, et al. 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