GSDME-N-induced mitochondrial neurotoxicity in early neurodegeneration was suppressed by nicotine via enhancing autophagic flux

  • J Transl Med. 2025 Oct 31;23(1):1202. doi: 10.1186/s12967-025-07247-y.
Junjun Zhao  #  1  2 ,  Saitao Qiu  #  2  3 ,  Angyang Guo  #  4 ,  Haixia Huang  1  2 ,  Wei Wang  5 ,  Jianliang Zhang  6  7
Affiliations
  • 1. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, #10 Xitoutiao, Youanmenwai, Beijing, 100069, China.
  • 2. Laboratory for Clinical Medicine, Capital Medical University, Beijing, China.
  • 3. Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, #10 Xitoutiao, Youanmenwai, Beijing, 100069, China.
  • 4. Department of Health Law, School of Medical Humanities, Capital Medical University, Beijing, China.
  • 5. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, #10 Xitoutiao, Youanmenwai, Beijing, 100069, China. [email protected].
  • 6. Laboratory for Clinical Medicine, Capital Medical University, Beijing, China. [email protected].
  • 7. Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, #10 Xitoutiao, Youanmenwai, Beijing, 100069, China. [email protected].
  • # Contributed equally.
PMID: 41174669 DOI: 10.1186/s12967-025-07247-y
Abstract

Background: Neurodegeneration is a chronic, progressive process initiated by early neurite retraction, a pathological hallmark preceding neuronal death in neurodegenerative disorders such as Parkinson’s disease (PD). Cleavage of gasdermin E (GSDME) releases its N-terminal domain (GSDME-N), which has been shown to mediate mitochondrial dysfunction and the onset of neurodegeneration. However, the therapeutic potential of targeting GSDME-N for early intervention in PD, and whether nicotine, a tobacco component with neuroprotective properties, acts through GSDME modulation remain unexplored.

Methods: The SH-SY5Y cells, primary neurons and C57BL mice were treated with rotenone to model neurodegeneration in PD. Mitochondrial accumulation of GSDME-N and activation of Autophagy were assessed via immunoblotting and immunostaining. Mitochondrial membrane potential was evaluated using JC-1 and TMRM fluorescent dyes, while mitochondrial Reactive Oxygen Species were detected with MitoSOX™ Red superoxide indicator. For morphological analysis, immunofluorescence staining was performed using antibodies against microtubule-associated protein 2 (MAP2) to visualize neurites, along with MitoTracker to label mitochondria within neurites. In vivo, C57BL/6 mice were administered rotenone and provided with nicotine supplementation in their drinking water. Motor function was assessed using rotarod, hanging wire and pole tests. Tyrosine Hydroxylase (TH)-positive neurons and fibers were detected using immunohistochemistry.

Results: We demonstrated that GSDME-N accumulation on mitochondria during early neurodegeneration was suppressed by nicotine, thereby maintaining mitochondrial homeostasis and preventing neurite retraction. Mechanistically, nicotine activated autophagic pathway to promote GSDME-N clearance, which maintained mitochondrial membrane potential, reduced Reactive Oxygen Species (ROS) production, and specifically rescued mitochondrial function. This protective mechanism significantly attenuated early pathological changes, including neurite retraction and loss. In a rotenone-induced PD model, nicotine treatment effectively reduced GSDME-N accumulation and decelerated neurodegenerative progression.

Conclusions: These findings reveal the critical role of GSDME-N in early-stage mitochondrial damage in PD and propose a novel therapeutic strategy targeting the nicotine-autophagy axis to counteract GSDME-N-mediated neurodegeneration.

Supplementary Information: The online version contains supplementary material available at 10.1186/s12967-025-07247-y.

Keywords
Autophagy; GSDME; Neurodegeneration; Nicotine.
Products