{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T15:52:42Z","timestamp":1783785162697,"version":"3.55.0"},"reference-count":76,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T00:00:00Z","timestamp":1772064000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["No. 32172786"],"award-info":[{"award-number":["No. 32172786"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Loss of ovarian hormones following menopause or ovariectomy is associated with increased anxiety, cognitive impairment, and dysregulation of hypothalamic neuroendocrine pathways. MicroRNAs (miRNAs) and tRNA-derived fragments (tRFs) are emerging classes of small non-coding RNAs that act as post-transcriptional regulators of stress, inflammation, and synaptic function; however, their coordinated involvement in estradiol-mediated hypothalamic regulation remains poorly understood. In this study, adult female mice were assigned to control, estradiol-treated, ovariectomized (OVX), or OVX plus estradiol groups. Anxiety- and cognition-related behaviors were assessed using the open field, Y-maze, and elevated plus maze tests. Circulating estradiol levels and hypothalamic gonadotropin-releasing hormone (GnRH) expression were quantified by ELISA. Hypothalamic mRNA, miRNA, and tRF expression profiles were analyzed by RNA sequencing, followed by differential expression analysis, functional enrichment, integrative network construction, and quantitative real-time PCR validation. Ovariectomy induced anxiety-like behaviors, impaired working memory, reduced estradiol levels, and increased hypothalamic GnRH expression, all of which were reversed by estradiol treatment. Transcriptomic analysis identified 376 differentially expressed miRNAs, 182 differentially expressed tRFs, and 439 differentially expressed mRNAs, enriched in pathways related to stress responses, neuroendocrine regulation, synaptic signaling, metabolic homeostasis, and neuroinflammation. Integrated miRNA\u2013mRNA and tRF\u2013mRNA network analyses revealed several estradiol-responsive miRNAs (including miR-200a-5p, miR-182\/183-5p, miR-381-3p, miR-148a-3p, and miR-10 family members) predicting key hub genes such as Gcg, Wnt4, Prkacb, Sgk1, Fpr2, and Aldoa, and key tRFs like tRFdb-1003, tRFdb-1013, tRFdb-1026, tRFdb-3001a and tRFdb-5020a, targeting hub genes such as Wnt4, Prkacb, Sh3rf2, Hpse, Cxcr2 and Zbtb16 respectively. Collectively, these findings demonstrate that estradiol ameliorates OVX-induced behavioral and endocrine dysfunction by reorganizing hypothalamic miRNA- and tRF-mediated regulatory networks involved in stress adaptation, synaptic homeostasis, and neuroimmune signaling.<\/jats:p>","DOI":"10.3390\/biom16030354","type":"journal-article","created":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T16:57:13Z","timestamp":1772125033000},"page":"354","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Estradiol Reverses Ovariectomy-Induced Small RNA\u2013mRNA Stress Signatures to Restore Neuroendocrine, Synaptic, and Immune Homeostasis in the Hypothalamus"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-0188-3496","authenticated-orcid":false,"given":"Muhammad","family":"Mubashir","sequence":"first","affiliation":[{"name":"College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Yang","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohuan","family":"Chao","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunlei","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahao","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Ding","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongwei","family":"Bi","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziming","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Guo","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junhong","family":"Fan","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengjun","family":"Zhou","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2857-8536","authenticated-orcid":false,"given":"Bo","family":"Zhou","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"108087","DOI":"10.1016\/j.maturitas.2024.108087","article-title":"Neuroendocrine mechanisms of mood disorders during menopause transition: A narrative review and future perspectives","volume":"188","author":"Fidecicchi","year":"2024","journal-title":"Maturitas"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1007\/s12264-021-00689-6","article-title":"Hypothalamic-pituitary-end-organ axes: Hormone function in female patients with major depressive disorder","volume":"37","author":"Zhu","year":"2021","journal-title":"Neurosci. 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