{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n The long noncoding RNA (lncRNA) HAS2‐AS1 has emerged as a multifunctional regulator that fine‐tunes hyaluronan (HA) synthesis and influences diverse cellular behaviors in a context‐dependent manner. In vascular smooth muscle and cumulus cells, HAS2‐AS1 modulates the transcription of its sense gene, HAS2, by altering local chromatin accessibility and recruiting transcription factors in response to metabolic cues such as O‐GlcNAcylation, thereby enhancing HA production and promoting cell migration."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In renal proximal tubular epithelial cells, coordinated induction of HAS2‐AS1 and HAS2 by IL‐1β and TGF‐β1 supports HAS2 mRNA expression via the formation of RNA heteroduplexes, suggesting a role in mRNA stabilization."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " In several cancer types—including oral squamous cell carcinoma, breast cancer, and glioma—HAS2‐AS1 expression is up‐regulated by hypoxia‐responsive factors (e.g., HIF‐1α), STAT1, USF1, and C/EBPβ, thereby promoting epithelial–mesenchymal transition (EMT), invasion, and migration by either stabilizing HAS2 or acting as a competing endogenous RNA that sequesters tumor‐suppressive microRNAs."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "9"}]}, {"type": "t", "text": " In contrast, studies in osteosarcoma and in certain estrogen receptor–negative breast cancer models have shown that specific splice variants of HAS2‐AS1 can down‐regulate HAS2 mRNA and HA synthesis, thereby reducing proliferation and aggressiveness."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Moreover, in lung fibroblasts under hypoxic conditions relevant to pulmonary hypertension, HAS2‐AS1 is induced by C/EBPβ and contributes to enhanced cell proliferation, migration, and inflammatory responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings indicate that HAS2‐AS1 orchestrates a variety of processes—from extracellular matrix remodeling and HA synthesis to the regulation of EMT and cell invasiveness—thereby impacting vascular pathologies, tumor progression, and other physiological functions in a context‐specific manner.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Davide Vigetti, Sara Deleonibus, Paola Moretto, et al. 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