Neurotoxicity refers to damage to the nervous system, which can lead to various clinical manifestations such as altered consciousness, motor function impairment, and cognitive decline. Neurotoxicity can be caused by a variety of factors, including drugs, toxins, and infections (Della Giovampaola et al., 2022). The neurotoxic mechanism of propofol mainly induces apoptosis, but the specific mechanism of its action is currently unclear and requires further research. The protein Drp1 plays a central role in regulating mitochondrial morphological changes, especially when cells respond to various physiological and pathological stimuli. Studies have shown that excessive activation of the Drp1 can lead to excessive mitochondrial fission, resulting in dysfunctional mitochondria, which in turn triggers apoptosis and tissue damage (Wang and Qiu, 2023; Zhang B.-F., et al., 2024). The dynamic balance of mitochondria relies on the coordination of fission and fusion processes. Drp1, by promoting mitochondrial fission, can help cells adapt to changes in energy demand and respond to challenges such as oxidative stress (Rosdah et al., 2020; Yang et al., 2022). The balance between mitochondrial fusion and fission is disrupted in hippocampal neuron injuries, and the main protein involved, Drp1, is linked to neurodevelopment, neural plasticity, and neurological issues (Gao et al., 2022). Drp1’s role in mitochondrial fission is essential for repairing injuries in hippocampal neurons. This article reviews the structure and function of Drp1, discusses its role in propofol neurotoxicity based on animal studies, examines the mechanistic link between Drp1 and neurotoxicity, analyzes Drp1’s involvement in mitochondrial dysfunction across different organs, and suggests targeting Drp1 as a strategy to prevent neurotoxicity. In summary, the discussion in this article provides important insights for the detection, prevention, and drug development of propofol-induced neurotoxicity from the perspective of Drp1.

Drp1 is an important GTPase that primarily participates in the division and dynamic regulation of mitochondria. Drp1 has multiple protein isoforms, which arise from the alternative splicing of pre-mRNA transcripts encoded by a single gene. The structure of Drp1 mainly consists of a GTPase domain, a GTP-binding domain, and a C-terminal helical domain. At its N-terminus, Drp1 also has a proline-rich region. The GTPase activity of Drp1 enables it to bind GTP and drive the mitochondrial division process through GTP hydrolysis. The domains of Drp1 play a crucial role not only in its self-assembly and activity regulation but also in regulating mitochondrial morphology and function through interactions with other proteins. Drp1 interacts with mitochondrial fission proteins such as Fis1, Mff, MiD49, and MiD51 (Nolden et al., 2023). For example, Drp1 promotes the process of mitochondrial fission by binding to adaptor proteins (such as Mff and Fis1) on the outer mitochondrial membrane through its C-terminal helical domain (Nolden et al., 2023; Torcasio et al., 2024). Research shows that the direct interaction between Fis1 and Drp1 can maintain mitochondrial morphology, with Fis1 influencing the balance of mitochondrial fission and fusion by regulating the assembly state of Drp1 (Choi et al., 2020; Egner et al., 2022). Drp1 is involved in the process of mitochondrial fission, including recruitment from the cytosol to the outer mitochondrial membrane (OMM), high-level self-assembly, GTP hydrolysis, and eventual fragmentation (Feng et al., 2020).

In recent years, it has been reported that the function of Drp1 is not limited to mitochondrial fission but also involves various biological processes in cells, including cellular stress responses, metabolic regulation, and apoptosis. There is evidence that mitochondria in the spinal dorsal horn (SDH) are sensitive to neuropathic pain (NP), and targeting mitochondrial Drp1 overexpression alleviates pain hypersensitivity, providing a new therapeutic target for pain treatment (Zhang K.-L., et al., 2022).

Abnormal levels or dysfunction of Drp1 are closely linked to the development of several diseases, including neurodegenerative disorders, cardiovascular diseases, and cancers (Zeng et al., 2020). Because the nervous system requires a large amount of energy, mitochondrial damage or dysfunction greatly affects neuronal activity and can even lead to their death.

Propofol’s toxic reactions extend beyond the nervous system, primarily causing dose-dependent suppression of the cardiovascular and respiratory systems, with symptoms such as hypotension, bradycardia, and apnea. An overdose can result in significant hypotension, arrhythmias, or even cardiac arrest. Moreover, prolonged high-dose use of propofol (exceeding 4 mg/kg/h) for over 48 h may trigger propofol infusion syndrome (PRIS), characterized by severe conditions such as metabolic acidosis, rhabdomyolysis, hyperkalemia, and multiple organ failure (Singh and Anjankar, 2022). Other possible adverse reactions include injection pain, allergic reactions, and, although rare, lipid metabolism disorders that can be fatal. The risk of toxicity significantly increases in children, critically ill patients, and with prolonged use, necessitating strict monitoring of vital signs and medication dosage. The corresponding toxic reactions of propofol on different organs are as follows.

Propofol is mainly metabolized in the liver, relying on hepatic blood flow, though extrahepatic metabolism also occurs (Kazi et al., 2025). In adults, UGT1A9 primarily mediates hepatic metabolism, whereas in neonates, cytochrome P450 plays a key role (Sandra et al., 2021). The use of propofol can produce ROS that overwhelm the body’s antioxidant defenses, leading to oxidative stress and potential liver damage. Research indicates that propofol doses exceeding clinical levels (e.g., an IC₅₀ of 254.904 μg/mL) can be toxic to hepatic fibroblasts (AML12) due to elevated intracellular ROS, which triggers mitochondrial pathways that lead to apoptosis (Pehlivan et al., 2023). Mitochondrial fission plays a crucial role in maintaining hepatocyte homeostasis and preventing liver tumorigenesis (Ma et al., 2025).

When activated, Drp1 moves to the mitochondria in cardiac cells, leading to significant mitochondrial division. The excessive fragmentation of mitochondria disrupts the structure of the heart and affects blood flow. This disruption can lead to multi-organ dysfunction and higher mortality rates (Liu et al., 2024). The main pathophysiological mechanism behind PRIS is the disruption of the mitochondrial respiratory chain, which hampers ATP synthesis and leads to cellular hypoxia. For example, propofol causes coenzyme Q-sensitive leakage in the mitochondria of cardiac myocytes. This leakage uncouples immature cardiomyocytes and disrupts coenzyme Q’s role in the electron transport chain (Barajas et al., 2022).

Furthermore, human embryonic kidney cells (HEK-293) serve as an excellent in vitro model for examining renal cell physiology. Studies indicate that with an increase in propofol dosage, there is a corresponding decline in cell viability alongside an increase in ROS, culminating in cell apoptosis and ultimately cell death (Pehlivan et al., 2024). Similar trends have been observed in other cell types, such as human promyelocytic leukemia cells, where elevated doses of isoflurane also hinder oxygen utilization and initiate apoptosis. The extent to which propofol exhibits either complete or primarily mitochondrial toxicity remains uncertain, particularly in individuals with mitochondrial defects. However, it can be inferred that in patients with pre-existing mitochondrial disorders, propofol may further aggravate mitochondrial dysfunction (Finsterer and Frank, 2016).

In summary, propofol causes varying degrees of damage to the nervous system, liver, heart, and kidneys. A deeper exploration of the effects of propofol on different systems and organs provides important clues for our comprehensive understanding of the toxic reactions of propofol.

The mitochondrial quality control system, which includes mitochondrial fusion and fission, mitophagy, and mitochondrial biogenesis, is crucial for maintaining mitochondrial homeostasis and function (Eldeeb et al., 2022). Mitochondrial fission is regulated by a series of proteins, with Drp1 being the dominant one. Overexpression of Drp1 leads to excessive mitochondrial fission, resulting in dysfunctional mitochondria. In neurons, abnormal mitochondrial fission is closely related to the occurrence of various neurodegenerative diseases such as Alzheimer’s disease (Joshi et al., 2018), Huntington’s disease (Roe and Qi, 2018), and Parkinson’s disease (Zhang et al., 2020). Therefore, inhibiting the overactivation of Drp1 or regulating mitochondrial dynamics is a method to promote neuroprotection (He et al., 2024).

It is known that astrocytes can release healthy mitochondria to migrate to damaged neurons to alleviate propofol-induced neurotoxicity. Inhibitors of Drp1, such as Mdivi-1, have been shown to weaken the effects of propofol on NSC proliferation, differentiation, apoptosis, and ROS production, as well as mitigate propofol-induced mitochondrial ultrastructural changes and MMP inhibition, effectively reducing pathological changes in neurodegenerative and metabolic diseases (Liang et al., 2021; Furuya et al., 2023; Sun et al., 2024). However, it is noteworthy that pretreatment with Mdivi-1 only partially attenuates, rather than completely reverses, propofol-induced cell death, which may be associated with the potential role of uninvestigated components. In contrast, pretreatment with the CDK1 inhibitor Roscovitine rescues propofol-induced cell death, Drp1 activation, and increased mitochondrial fission (Hogarth et al., 2023). Hypoxic preconditioning can increase the expression of pDrp1 protein and glucose transporters (GLUT1 and GLUT3), providing neuroprotection and promoting brain recovery (Xiao et al., 2020). Pharmacological activation of AMPK using agents such as AICAR effectively suppresses propofol-induced p53 expression and subsequent apoptotic signaling activation, thereby attenuating propofol-mediated neurotoxicity (Xiao et al., 2022). Experimental evidence demonstrates that Liuwei Dihuang Wan enhances cognitive function and confers neuroprotective effects against brain aging by modulating mitochondrial dynamics. Specifically, LDW upregulates mitochondrial fusion proteins while downregulating Drp1 expression, thereby attenuating mitochondrial impairment and restoring the balance between mitochondrial fusion and fission (Wang et al., 2023).

To fully understand the regulatory mechanisms of Drp1, future research needs to employ various technical approaches, including gene editing, protein interaction analysis, and metabolomics, to reveal the functions of Drp1 under different physiological and pathological conditions. The widespread application of CRISPR/Cas9 gene editing technology allows researchers to quickly construct cell models to explore the roles of specific genes in the cell cycle and apoptosis. Additionally, the emergence of single-cell RNA sequencing technology enables researchers to analyze the dynamic changes in gene expression during the cell cycle and apoptosis at the single-cell level. Furthermore, exploring the combined application of Drp1 with other neurotoxic markers (such as Pink1 and Mfn2) will help improve the predictive and detection capabilities of propofol neurotoxicity and provide references for clinical translational research (Froehlich et al., 2024). The ways in which Drp1 influences Bax and Bcl-2 to initiate the caspase cascade reaction, thereby triggering neuronal apoptosis, also need to be explored in depth in the future. A critical question warranting further investigation is whether the combined use of anesthetic agents in clinical practice elicits differential Drp1-mediated effects on neuronal cells compared to propofol monotherapy.

Drp1 reduces the neurotoxicity of propofol by decreasing the production of ROS, adjusting the phosphorylation state of Drp1 to affect the cell cycle, regulating signaling pathways, and activating autophagy. However, the mechanisms and intrinsic relationships among these factors still require further investigation. There is considerable evidence from animal experiments and in vitro studies, but a lack of data at the human level. Although propofol exposure causes damage to developing hippocampal neurons, the mechanisms are not yet clear, but current research evidence points to changes in the expression of apoptosis-related proteins such as Bcl-2 and Bax, thereby affecting neuronal survival. However, this paper has limited clinical relevance and human data references, as it mainly relies on animal studies. As the research advances, we will better understand propofol’s neurotoxicity during human development and how Drp1 regulates this neurotoxicity.