{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Hyaluronan synthase‐3 (HAS3) is a transmembrane enzyme responsible for synthesizing hyaluronan (HA), a key glycosaminoglycan component of the extracellular matrix that governs tissue remodeling, cell–cell adhesion and signal transduction. A growing body of evidence indicates that HAS3‐mediated HA production is critically involved in diverse physiologic and pathologic processes.\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the cardiovascular system, a common genetic variant in HAS3 was shown to modify anthracycline‐induced cardiomyopathy risk, possibly by affecting HA‐dependent tissue remodeling and reactive oxygen species scavenging."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In addition, endothelial HAS3 contributes to arteriogenesis by promoting HA–CD44 signaling that stimulates eNOS phosphorylation and improves flow‐mediated dilation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In several cancers, HAS3 plays multifaceted roles. Overexpression of HAS3 augments HA accumulation in pancreatic"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ", colon"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ";"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ", oral"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ", melanoma"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "and glioma"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ", where it modulates cellular adhesion, migration and invasion through remodeling of the pericellular matrix. In some instances, microRNAs (for example, miR‐29a–3p and miR‐10a–5p) can target HAS3 to suppress malignant properties in gastric cancer"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "and in atopic dermatitis‐associated keratinocyte proliferation"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ", underscoring a context‐dependent role in tumor progression.\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the skin and other epithelia, HAS3 expression is tightly regulated by cytokines and environmental stimuli. Increased HAS3 expression in keratinocytes is associated with enhanced HA synthesis, which may disturb E‐cadherin–mediated cell adhesion and contribute to spongiosis in acute eczema."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " Conversely, restoration or induction of HAS3 expression by agents such as saponarin"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "and paprika xanthophylls"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "correlates with improved skin barrier function and moisture. Moreover, in dermatoporotic skin, increased HAS3 transcript levels after topical treatment have been linked to enhanced skin thickness and barrier restoration"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": ", while cytokine‐mediated regulation underscores its predominant role in epidermal HA synthesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n HAS3 is also central to vascular and airway biology. In vascular smooth muscle cells, HAS3‐driven HA production promotes platelet‐derived growth factor BB–mediated migration and neointimal hyperplasia"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": ", whereas in the lung, mechanical stretch and injurious ventilation induce HAS3 expression in fibroblasts, leading to the production of low–molecular weight HA that stimulates proinflammatory cytokine release."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": " Furthermore, increased HAS3 expression in airway epithelial and smooth muscle cells has been linked to neonatal CPAP–induced airway hyper‐reactivity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In developmental morphogenesis, HAS3‐generated HA can generate osmotic pressure to drive epithelial invagination and tissue shaping, as elegantly demonstrated in zebrafish semicircular canal formation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, HAS3 influences intercellular communication by promoting the shedding of extracellular vesicles enriched in HA and signaling molecules, which in turn modulate recipient cell proliferation and epithelial–mesenchymal transitions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "20", "end_ref": "22"}]}, {"type": "t", "text": " Taken together, these findings highlight HAS3 as a pivotal regulator of HA production that influences a wide spectrum of processes—including cardiovascular remodeling, tumor progression, inflammatory skin conditions, vascular and airway responses, and developmental morphogenesis. Its expression is modulated by cytokines, mechanical forces, and microRNAs, making HAS3 a promising therapeutic target in a variety of clinical settings.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Xuexia Wang, Wei Liu, Can-Lan Sun, et al. 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