ACSL1‐Dependent Microglial Lipoimmunometabolic Reprogramming Underlies Cognitive Deficits in Alcohol Use Disorder
Source abstract
Abstract
ABSTRACT Alcohol use disorder (AUD) leads to cognitive impairment dependent on prefrontal cortex (PFC) dysfunction, yet the underlying cellular and molecular mechanisms, particularly the role of microglia, remain poorly understood. Through re‐analysis of single‐cell RNA sequencing data from AUD patients, we identified aberrant activation of lipid metabolic pathways in microglia and pinpointed acyl‐CoA synthetase long‐chain family member 1 (ACSL1) as a central regulator. In animal and cellular models, chronic ethanol exposure induced ACSL1 upregulation, triggering lipid droplet accumulation, neuroinflammatory activation, and aberrant microglia–neuron interactions mediated via PTPRM signaling. Pharmacological inhibition of ACSL1 reversed these pathological phenotypes. We further developed a dual‐targeted lipid nanoparticle system for microglia‐specific ACSL1 silencing, which effectively ameliorated ethanol‐induced cognitive deficits in mice. Our study unveils ACSL1‐mediated lipoimmunity reprogramming of microglia as a core mechanism underlying cognitive impairment in AUD and proposes a novel targeted therapeutic strategy.
Source: crossref · Quality: baseline
Research context
OpenAlex topics: Neuroinflammation and Neurodegeneration Mechanisms · Alcoholism and Thiamine Deficiency · Neurogenesis and neuroplasticity mechanisms
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
Affiliations
Department of Chemistry School of Forensic Medicine China Medical University Shenyang China
Liaoning Province Key Laboratory of Forensic Bio‐Evidence Sciences Shenyang China
Department of Biochemistry & Molecular Biology China Medical University Shenyang China
Key Laboratory of Cell Biology, and Key Laboratory of Medical Cell Biology Ministry of Public Health Ministry of Education China Medical University Shenyang China
National Clinical Research Center for Laboratory Medicine Department of Laboratory Medicine The First Hospital of China Medical University Shenyang China
Department of Endocrinology & Metabolism The First Hospital of China Medical University Shenyang China
Department of Forensic Pathology School of Forensic Medicine China Medical University Shenyang China
Funding
National Natural Science Foundation of China · Natural Science Foundation of Liaoning Province
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