{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Hyaluronan synthase‐1 (HAS1) is one of three homologous enzymes responsible for coupling cytosolic UDP–sugar substrates into hyaluronan (HA), a glycosaminoglycan that is central to extracellular matrix structure and intracellular signaling. Although HAS1 generally displays lower basal activity than HAS2 and HAS3, its function becomes critical under conditions of cellular stress, increased substrate availability, and inflammatory stimulation. In several cell types—including synoviocytes, macrophages, and epithelial cells—HAS1 expression is up‐regulated by pro‐inflammatory cytokines and is controlled by pathways such as NF‑κB and Toll‑like receptor signals ("}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "). In pathological contexts, aberrant splicing of HAS1 produces variant isoforms that alter its intracellular localization, protein stability, and HA‐synthesizing activity. Such splice variants have been detected in hematologic malignancies (including multiple myeloma, Waldenström macroglobulinemia, and certain B‐cell cancers), as well as in solid tumors such as bladder cancer and melanoma, where they are associated with increased intracellular HA accumulation, genomic instability, and a more aggressive phenotype ("}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "8"}]}, {"type": "t", "text": ")."}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition, HAS1-mediated HA synthesis contributes to tissue remodeling and immune regulation. Its expression is modulated by metabolic and hormonal cues—for example, high-glucose conditions and estrogen signaling can affect HA chain length and the composition of the HA coat, thereby influencing cellular adhesion, migration, and proliferation ("}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "). Moreover, studies in joint and lung tissues indicate that HAS1 plays a role in fibrotic responses and repair processes, and its absence or dysregulation can impair effective healing ("}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ")."}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its contribution to pathology, HAS1 is emerging as an important target in regenerative and aesthetic medicine. Up-regulation of HAS1 in dermal fibroblasts is linked to enhanced extracellular matrix synthesis and improved skin hydration, while its modulation in engineered tissue platforms appears to favor more effective cartilage repair ("}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "14"}]}, {"type": "t", "text": "). Collectively, these studies highlight the multifunctional role of HAS1—not only as an enzyme responsible for HA synthesis but also as a modulator of cellular behavior in inflammation, tissue remodeling, and oncogenesis. Consequently, both the canonical and aberrant splice forms of HAS1 are being investigated as potential diagnostic markers and therapeutic targets in a range of pathologic states ("}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "17"}]}, {"type": "t", "text": ").\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Janet J Kao "}, {"type": "b", "children": [{"type": "t", "text": "The NF-kappaB inhibitor pyrrolidine dithiocarbamate blocks IL-1beta induced hyaluronan synthase 1 (HAS1) mRNA transcription, pointing at NF-kappaB dependence of the gene HAS1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Exp Gerontol (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.exger.2006.04.003"}], "href": "https://doi.org/10.1016/j.exger.2006.04.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16723203"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16723203"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Mary Y Chang, Inkyung Kang, Michael Gale, et al. 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