2. Academic Validation
  3. Acetylation of fatty acid synthase regulates microglial lipid droplets accumulation and pro-inflammatory activity following traumatic brain injury

Acetylation of fatty acid synthase regulates microglial lipid droplets accumulation and pro-inflammatory activity following traumatic brain injury

  • Redox Biol. 2025 Dec 15:89:103978. doi: 10.1016/j.redox.2025.103978.
Fengchen Zhang 1,  Tao Lv 2,  Tianqi Xu 3,  Jie Li 3,  Jie Lian 3,  Siyu Lin 4,  Qin Hu 3,  Yichao Jin 5,  Feng Jia 6,  Xiaohua Zhang 7
Affiliations

Affiliations

  • 1 Department of Neurosurgery, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China. Electronic address: [email protected].
  • 2 Department of Neurosurgery, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China. Electronic address: [email protected].
  • 3 Department of Neurosurgery, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
  • 4 Department of Endocrinology and Metabolism, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
  • 5 Department of Neurosurgery, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China. Electronic address: [email protected].
  • 6 Department of Neurosurgery, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China; Department of Neurosurgery, Nantong First People's Hospital, Affiliated Hospital 2 of Nantong University, Nantong, Jiangsu, 226001, China. Electronic address: [email protected].
  • 7 Department of Neurosurgery, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China. Electronic address: [email protected].
PMID: 41412037 DOI: 10.1016/j.redox.2025.103978
Abstract

Lipid droplet accumulation in microglia has been implicated in inflammatory functions associated with aging and demyelinating diseases. However, the molecular mechanisms driving lipid droplet formation under pathological conditions remain unrevealed. It is demonstrated herein that the acetylation of fatty acid synthase (FASN) plays a key regulatory role in the accumulation of lipid droplets in microglia following traumatic brain injury (TBI). Through mass spectrometry analysis, we identified hyperacetylation at lysine K673 of FASN as a critical driver of lipid droplet formation in microglia. Notably, this acetylation event not only promotes lipid droplet accumulation but also enhances pro-inflammatory cytokine production and phagocytic activity in microglia. Additionally, we found that HDAC3 may be the enzyme responsible for deacetylation of FASN K673. Importantly, observation of a mouse model carrying the FASN K673R mutation revealed a reduction in microglial lipid droplet accumulation and neuroinflammatory responses following TBI relative to wild-type mice. Thus, FASN acetylation is a pivotal regulator of post-TBI microglial lipid droplet formation and neuroinflammation. This positions the targeting of deacetylation pathways as a novel therapeutic strategy for TBI.

Keywords

Acetylation; Fatty acid synthase; Microglia; Neuroinflammation; Traumatic brain injury.

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