The central nervous system (CNS), which is composed of the brain and the spinal cord, is highly sensitive to external mechanical damage. Acute CNS injury, which mainly includes traumatic brain injury (TBI), spinal cord injury (SCI), subarachnoid haemorrhage (SAH) and hypoxic–ischaemic encephalopathy (HIE), is a leading cause of death and disability worldwide [
1‐
4]. Acute CNS damage is associated with a tremendous social and economic expenditure and costs the medical system across the world more than US $200 billion each year [
5]. Clinically, the conventional neuroprotective therapies for CNS injury mainly attempt to relieve mechanical compression by surgery combined with hyperbaric oxygen therapy, high-dose methylprednisolone, nerve dehydration and other comprehensive programmes [
6‐
8]. Basic research has revealed potential treatments such as growth factors, tissue engineering, cell transplantation and neuroinflammation inhibitors [
9‐
11], but major breakthroughs have not yet been achieved. Although these therapeutic measures alleviate the loss of neurological function to a certain extent, the long-term prognosis of CNS injury and the recovery of neurological function are still not optimistic. CNS injury is characterized by two temporal and spatial developments, including primary injury and secondary injury. Primary injury occurs when damage occurs and includes the cutting/tearing/extension of axons [
12]. The primary physical lesion causes cell strain and membrane injury, which results in an imbalance of ions, the release of excitant amino acids, and oxidative species generation in the injured region [
13,
14]. These processes trigger secondary injury that jointly extend the damage to healthy adjacent cells, leading to inflammation and neuronal cell death and eventually to loss of function [
15]. Hence, apoptosis and subsequent inflammatory processes are prime biological mechanisms underlying CNS damage. Identifying methods for regulating neuroinflammation to alleviate the death of nerve cells is key in the treatment of CNS injury. The disruption of cellular homeostasis could induce cumulative cytoplasmic DNA, such as DNA lesions, disrupted mitochondria and exosomes, in which cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) senses and is stimulated with the combination of double-stranded DNA (dsDNA) [
16,
17]. Specifically, cGAMP and other cyclic dinucleotides (CDNs) propagate the signal to the endoplasmic reticulum (ER) protein called stimulator of interferons genes (STING). STING was first described as a protein that interacts with major histocompatibility complex class II molecules, but the relevance of this interaction remains unclear [
18]. To further determine the origin of proteins that overexpress interferon-β (IFN-β), Ishikawa et al. employed an expression screening system to identifying proteins able to induce interferon-β (IFN-β) secretion, and in the study, approximately 5500 human and 9000 murine full-length cDNAs were individually transfected into cells harbouring a luciferase gene under the control of the IFNβ promoter [
19]. Five genes whose overexpression led to significant induction of IFNβ were found, and one of the previously uncharacterized molecules is denoted STING by the authors [
19]. Subsequent study of STING-deficient mice confirmed the essential role of STING in innate responses to stimulate IFNβ [
20]. STING dimerizes and translocates from the ER to perinuclear structures, such as the Golgi apparatus. STING binds to TANK-binding kinase 1 (TBK1), which results in its phosphorylation. Phosphorylated STING then binds to positively charged surfaces of interferon regulatory factor 3 (IRF3), which leads to its phosphorylation and activation by TBK1 [
21]. The phosphorylation of IRF3 induces the translocation of IRF-3 from the cytoplasm to the nucleus. IRF-3 binds to the IFN-stimulated response element of the IFN-stimulated gene 15 (ISG15) promoter and increases its transcriptional activation [
22]. Afterward, the signal peaks in interferon regulatory factor 3 (IRF3) and NF-κB targets, causing IFN secretion [
23]. Furthermore, some evidence verifies the significance of IFN in neuroinflammation and cell death, which implies the disruption of IFN responses in different immunity-regulated disorders, such as CNS injury [
24]. It has been revealed the essential role of cGAS–STING, which signals a primary inducing factor of IFNs for cytosolic DNA or CDNs [
25]. Nevertheless, whether the cGAS/STING/IFN axis facilitates the pathogenesis of CNS injury still needs investigation. Our research initially discusses the cGAS–STING pathway and studies targeting the participation of STING in CNS injury. Moreover, we examine the functions of the cGAS–STING pathway in the IFN immune response and certain cell death pathways, such as autophagy, necroptosis, ferroptosis and pyroptosis. Additionally, we highlight the molecular mechanisms and biological roles of cGAS–STING pathway activation to reinforce the biotherapeutic validity of cGAS–STING in CNS damage. We ultimately aim to provide a more in-depth understanding of the mechanism through which STING signalling modulates the nerve inflammatory response in CNS injury and thus reveal the underlying therapeutic value of the cGAS–STING pathway in acute CNS damage.