Sevoflurane-induced neurotoxicity in neonatal mice is driven by microglial ferroptosis via MSTRG.7388-dependent NCOA4/STING axis

  • Neuropharmacology. 2026 Aug 15:294:110978. doi: 10.1016/j.neuropharm.2026.110978.
Qi Zhang  1 ,  Jiahui Ma  2 ,  Yi Gao  3 ,  Jiajie Zhang  4 ,  Zhenzhen Cai  4 ,  Lei Shi  5 ,  Yanan Li  6 ,  Zhiyong Hou  7
Affiliations
  • 1. Postdoctoral Mobile Station of the Third Hospital of Hebei Medical University, Shijiazhuang City, Hebei, 050051, China; Department of Anesthesiology, Hebei Children's Hospital, Shijiazhuang City, Hebei Province, 050031, China.
  • 2. Department of Anesthesiology, Peking University First Hospital, Beijing, 100034, China.
  • 3. Department of Anesthesiology, Shijiazhuang Obstetrics and Gynecology Hospital, Shijiazhuang City, Hebei Province, 050035, China.
  • 4. Department of Anesthesiology, Hebei Children's Hospital, Shijiazhuang City, Hebei Province, 050031, China; Graduate School of Hebei Medical University, Shijiazhuang City, Hebei Province, 050011, China.
  • 5. Department of Anesthesiology, Hebei Children's Hospital, Shijiazhuang City, Hebei Province, 050031, China. Electronic address: [email protected].
  • 6. Department of Anesthesiology, The Third Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province, 050051, China. Electronic address: [email protected].
  • 7. Department of Orthopaedic Surgery, Third Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province, China; Engineering Research Center of Orthopedic Minimally Invasive Intelligent Equipment, China Ministry of Education, China; Key Laboratory of Precise Assessment, Diagnosis, and Treament of Soft Tissue Injury of Hebei Province, China. Electronic address: [email protected].
PMID: 42009246 DOI: 10.1016/j.neuropharm.2026.110978
Abstract

Preclinical investigations have indicated that recurrent sevoflurane exposure induces long-term cognitive deficits in neonatal mice while the effects of inhalational anesthetics on children remain ambiguous. In the current study, Our comprehensive analysis of single-nucleus transcriptomics-guided competing endogenous RNA (ceRNA) networks revealed long-stranded ncRNA (lncRNA) MSTRG.7388 as a pivotal modulator in sevoflurane-mediated cognitive impairment, regulating microglial activation through the inhibition of MicroRNA miR-410-3p and the promotion of nuclear receptor coactivator 4 (NCOA4) expression. Furthermore, we elucidated that mutual binding of NCOA4 and stimulator of interferon genes (STING) dimers induced microglial Ferroptosis independent of the ubiquitination pathway and long-term cognitive impairment in mice exposed to sevoflurane. Notably, either the knockdown of NCOA4 or the administration of Fe2+ scavengers (iron chelators) reversed these effects. Collectively, these findings demonstrate that repeated sevoflurane exposure leads to long-term cognitive impairment in neonatal mice by aggravating microglial Ferroptosis via the MSTRG.7388/miR-410-3p/NCOA4/STING signaling axis.

Keywords
Cognitive dysfunction; Ferroptosis; Microglia; NCOA4; STING; Sevoflurane.
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