{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMicroRNA‐661 has emerged as an important regulatory molecule in non‐cancerous and metabolic disorders. Its serum levels are elevated in type 2 diabetes mellitus, particularly in patients with microvascular complications, and similar upregulation has been observed in diabetic foot ulcers, suggesting its potential as an early biomarker in such conditions. In myelodysplastic syndromes, high miR‐661 expression is associated with increased p53‐dependent apoptosis and poorer overall survival. Moreover, blastocyst‐secreted miR‐661 can be taken up by endometrial epithelial cells to downregulate MDM2 and impair cell adhesion, hinting at a role in implantation and infertility. Early investigations have also extended into vascular and inflammatory settings, although these findings remain preliminary."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn several cancer settings, miR‐661 exerts tumor‐suppressive functions. In glioma cells, forced expression of miR‐661 suppresses proliferation, migration, and invasion by directly targeting hTERT. In breast cancer cells, miR‐661 reduces the metastatic potential by inhibiting the expression of metastatic tumor antigen 1, with its own expression being positively regulated by the c/EBPα transcription factor. Furthermore, miR‐661 targets the 3′ untranslated regions of both Mdm2 and Mdm4, thereby modulating p53 activity and cell cycle progression; intriguingly, this effect appears to be cell context dependent, as p53‐mutated settings may instead favor enhanced migration."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nConversely, a body of evidence also supports an oncogenic role for miR‐661 in certain cancers. In ovarian cancer, elevated miR‐661 levels promote tumor cell proliferation by directly targeting INPP5J and concomitantly activating the AKT pathway. In non‐small cell lung cancer (NSCLC), contrasting reports have emerged: one study associates miR‐661 overexpression with enhanced proliferation and invasion through the direct repression of RUNX3, while another finds that restoration of a related form of miR‐661 induces G2 arrest via targeting UbcH10. In colon cancer, miR‐661 overexpression reprograms cellular metabolism by increasing mitochondrial reactive oxygen species and inducing an epithelial‐to‐mesenchymal transition, thereby contributing to a more aggressive tumor phenotype."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nA recurrent theme in recent studies is the modulation of miR‐661 activity by various circular RNAs (circRNAs) that act as competing endogenous RNAs. In triple‐negative breast cancer, circ‑UBAP2 sponges miR‐661 to relieve its suppression of MTA1, thereby driving tumor progression. Similar regulatory mechanisms have been documented in other cell types and malignancies: in vascular smooth muscle cells, circ_RUSC2 binds miR‐661 to influence the expression of SYK; in NSCLC and melanoma, circ_0001947 and circ_0103232 sequester miR‐661 to modulate downstream targets such as DOK7 and RAB3D, respectively; and in keloid fibroblasts as well as in lung cancer and osteosarcoma, circPDE7B, circ_0080608, and circSATB2 regulate miR‐661–dependent pathways that affect FGF2, ADRA1A, and FUS/ZNFX1 expression and consequently alter cell proliferation, invasion, and disease progression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "21"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, it is noteworthy that in some contexts the precise function of miR‐661 remains to be fully elucidated. For example, while investigations in Alzheimer’s disease suggest that its role is still poorly understood, other studies in osteosarcoma have focused on alternative molecular targets such as CYC1 without directly implicating miR‐661. These observations underscore the context‐dependent and multifaceted nature of miR‐661 regulation, highlighting the need for further research to clarify its tissue‐specific roles and therapeutic potential."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Cheng Wang, Shujun Wan, Ting Yang, et al. 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