{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n The long non‐coding RNA "}, {"type": "b", "children": [{"type": "t", "text": "HAND2‑AS1"}]}, {"type": "t", "text": " has emerged as an important regulator in both malignant and non‐malignant diseases. In several human cancers—including endometrioid endometrial, colorectal, esophageal, cervical, non‐small cell lung, breast, gastric, ovarian, glioma, and rectal carcinomas—HAND2‑AS1 expression is markedly downregulated and its lower levels correlate with advanced stage and poor prognosis. In these settings, HAND2‑AS1 acts predominantly as a tumor suppressor by “sponging” oncogenic microRNAs (for example, miR‑1275, miR‑21, miR‑143‑3p, miR‑106a, miR‑300, miR‑146, miR‑769‑5p, and miR‑3118) to restore the expression of key tumor‐suppressive proteins (such as KLF14, TNFAIP3, TIMP3, SOCS5, RUNX2, PHLPP2, and RARB) and by modulating signaling pathways including TGF‑β, PI3K/Akt, NF‑κB, and others."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "11"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In contrast, one study in liver cancer reported a context‐dependent, oncogenic role for HAND2‑AS1 because it is highly expressed in liver cancer stem cells and facilitates their self‐renewal by recruiting a chromatin‐remodeling complex to activate BMPR1A and downstream bone morphogenetic protein (BMP) signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " Notably, additional investigations in hepatocellular carcinoma have described HAND2‑AS1 as a tumor suppressor that, when overexpressed, inhibits cancer cell proliferation and triggers apoptotic pathways via modulation of the miR‑300/SOCS5 axis or by downregulating ROCK2."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "16"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond cancer, HAND2‑AS1 plays roles in non‐neoplastic conditions. In rheumatoid arthritis, for example, HAND2‑AS1 delivered via mesenchymal stem cell exosomes suppresses synoviocyte proliferation, motility, and inflammation by sponging miR‑143‑3p to upregulate TNFAIP3 and inhibit NF‑κB signaling"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": "may be cross‐referenced with related studies such as"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": "for reviews on cancer, although the RA study is distinct). In atherosclerosis, HAND2‑AS1 is decreased in patient plasma and in ox‑LDL–stimulated macrophages, where its overexpression limits foam cell formation by sponging miR‑128, thereby enhancing SIRT1 expression and promoting cholesterol efflux."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": " Moreover, lower HAND2‑AS1 levels in end‐stage dilated cardiomyopathy are associated with reduced insulin‑like growth factor‑1 levels and poor survival."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": " In osteoarthritis, HAND2‑AS1 expression declines with aging and disease progression; its overexpression in chondrocytes suppresses IL‑6 production, suggesting a role in modulating inflammatory responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, genetic deletions encompassing both HAND2 and HAND2‑AS1 have been linked to congenital heart defects, highlighting their contribution to normal cardiac development."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": " Additional studies in glioma, gastric, and bladder cancers further support its function as a competing endogenous RNA (ceRNA) that modulates key regulators of cell cycle progression (e.g. CDK6), apoptosis, and cell–cell adhesion."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "24", "end_ref": "26"}]}, {"type": "t", "text": " Moreover, analyses in rectal cancer reveal that HAND2‑AS1 is part of an lncRNA–mRNA regulatory network with potential prognostic implications"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "27"}]}, {"type": "t", "text": ", and emerging data indicate that it may also influence cancer stem cell functions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "28"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, HAND2‑AS1 displays multifaceted, context‐dependent roles. Depending on the tissue type and molecular milieu, it can function either as an oncogenic factor—promoting cancer stem cell self‐renewal (1)—or as a tumor suppressor that antagonizes malignant progression through ceRNA mechanisms (2–12, 14–16, 22–24, 26). Moreover, its regulatory influence on inflammatory signaling and lipid metabolism underscores its potential as a biomarker and therapeutic target in cardiovascular and degenerative joint diseases."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}, {"type": "fg_f", "ref": "19"}, {"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": " \n Collectively, these studies highlight the critical, yet context‐dependent, contributions of HAND2‑AS1 to human disease pathogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}, {"type": "fg_f", "ref": "4"}, {"type": "fg_f", "ref": "6"}, {"type": "fg_f", "ref": "9"}, {"type": "fg_f", "ref": "17"}, {"type": "fg_f", "ref": "23"}, {"type": "fg_f", "ref": "20"}, {"type": "fg_f", "ref": "26"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Xueying Yang, Chi Chiu Wang, Wayne Yuk Wai Lee, et al. 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