{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMicroRNA‐138 (also referred to here as SPMIP8) is emerging as a multifunctional regulator in the nervous and cardiovascular systems. In neuronal cells, it has been shown to suppress axon regeneration by targeting factors such as SIRT1, thereby establishing a mutual negative feedback loop that limits regenerative capacity (for example, see"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "and."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " In neural stem cells its downregulation correlates with enhanced proliferation and differentiation"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ", and although its expression is developmentally induced in Schwann cells, conditional loss of miR‐138 did not overtly perturb myelination."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " In models of cardiac injury, over‐expression of miR‐138 protects cardiomyocytes from hypoxia‐induced apoptosis by targeting pro‐apoptotic molecules like Lcn2"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ", while in the context of herpes simplex virus infection, miR‐138 dampens lytic replication in neurons by repressing viral immediate‐early gene expression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Moreover, modulation of additional targets such as MLK3 in oxidative stress–challenged microglia further underscores its role in fine‐tuning stress responses"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ", and miR‐138 also influences cardiac remodeling, as seen by its regulation of leukotriene B4 receptor 1 under myocardial ischemia–reperfusion conditions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn musculoskeletal, reproductive, and inflammatory contexts miR‐138 serves as a key “brake” on differentiation and inflammatory signaling. In mesenchymal stem cells, downregulation of miR‐138 is required for the full osteogenic response through activation of the FAK‐ERK1/2‐RUNX2 cascade"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ", whereas its elevation under oxidative or mechanical stress has been linked to impaired osteoblast survival and function"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "and."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " In endometriosis and osteoarthritis models, altered miR‐138 levels modulate inflammatory pathways such as NF‐κB and WNT/β‐catenin by targeting regulators like NEK2, ultimately affecting cell proliferation, apoptosis, and extracellular matrix homeostasis"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "and."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " In addition, a long noncoding RNA (Gm2044) sequesters miR‐138‐5p to promote estradiol synthesis in ovarian granulosa cells"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": ", while excessive miR‐138 expression contributes to injury in acute lung and diabetic nephropathy models by targeting SIRT1 and perturbing downstream mediators such as TTP"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "and."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": " Finally, by regulating epithelial‐to‐mesenchymal transition through ZEB2, miR‐138 can mitigate pulmonary fibrosis induced by toxic insults"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": ", and in the setting of opioid exposure its extracellular vesicle–mediated release activates microglia via TLR7."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Erick T Tatro, Victoria Risbrough, Benchawanna Soontornniyomkij, et al. 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