2. Academic Validation
  3. Steroid receptor RNA activator enhances hippocampal/amygdaloid PPARδ transcription to counteract anxiety disorders in female mice

Steroid receptor RNA activator enhances hippocampal/amygdaloid PPARδ transcription to counteract anxiety disorders in female mice

  • Biochem Biophys Res Commun. 2025 Oct 30:786:152737. doi: 10.1016/j.bbrc.2025.152737.
Yu Song 1,  Luyao Yang 2,  Bin Xu 3,  Boyuan Jiang 1,  Yang Yang 1,  Haifang Zhao 1,  Yinyin Ding 4,  Liang Sheng 5,  Keshu Cai 6,  Jing Jin 7
Affiliations

Affiliations

  • 1 School of Pharmacy, Xinxiang Medical University, Xinxiang, Henan, 453003, China.
  • 2 Department of Pharmacology, School of Basic Medical Science, Nanjing Medical University, Nanjing, Jiangsu, 211166, China.
  • 3 Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.
  • 4 Department of Gynecology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
  • 5 Department of Pharmacology, School of Basic Medical Science, Nanjing Medical University, Nanjing, Jiangsu, 211166, China. Electronic address: lgsheng@njmu.edu.cn.
  • 6 Department of Rehabilitation Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China. Electronic address: caikrshu@sina.com.cn.
  • 7 Department of Gynecology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China. Electronic address: jinjing@njucm.edu.cn.
PMID: 41056879 DOI: 10.1016/j.bbrc.2025.152737
Abstract

Anxiety disorders, with heightened female prevalence, are closely linked to neuroinflammatory dysregulation. This study elucidates the anti-anxiety mechanism of steroid receptor RNA activator (SRA), a long non-coding RNA, through its modulation of inflammatory pathways. In female SRA knockout mice, anxiety-like behaviors correlated with reduced Peroxisome Proliferator-activated Receptor δ (PPARδ) expression in the hippocampus and amygdala, key regions for neuroinflammatory regulation. Mechanistically, SRA directly enhanced nuclear factor κB (NF-κB)-dependent PPARδ transcription, independent of estrogen or Akt/inhibitor of nuclear factor κB kinase subunit β (IKKβ) signaling. This SRA/NF-κB/PPARδ axis suppressed neuroinflammatory cascades, as PPARδ agonism (GW0742) or SRA reconstitution reversed anxiety phenotypes and restored PPARδ levels. Notably, androgens in males masked SRA deficiency's role by autonomously upregulating PPARδ, underscoring sex-specific vulnerability. Although SRA deficiency in females exacerbated inflammation-associated anxiety, ovariectomy confirmed estrogen-independent regulation by SRA. These findings highlight SRA as a critical modulator of neuroinflammatory resilience via NF-κB/PPARδ signaling, offering novel therapeutic avenues for sex-biased anxiety disorders tied to inflammatory pathophysiology.

Keywords

Anxiety disorders; Neuroinflammation; PPARδ; SRA.

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