The effects of abused drugs on ferroptosis pathways: potential therapeutic targets for substance use disorders
1Department of Biological and Translational Department, Macon and Joan Brock Eastern Virginia Medical School/Virginia Health Sciences, Old Dominion University, Norfolk, VA, United States
2Keck School of Medicine of the University of Southern California, Los Angeles, CA, United States
3Center for Integrative Neuroscience and Inflammatory Diseases, Eastern Virginia Medical School/Virginia Health Sciences, Old Dominion University, Norfolk, VA, United States
*Correspondence: Ming-Lei Guo, GuoM@odu.eduAbstract
Substance use disorders (SUDs) remain major public health concerns worldwide, particularly in developed countries. SUDs are characterized by persistent neuroinflammation and synaptic dysfunction in the brain. Despite decades of extensive investigation, the detailed mechanisms underlying SUDs remain elusive. Ferroptosis is a highly regulated cell death process deeply affected by iron metabolism, lipid peroxidation, reactive oxygen species (ROS) production, and antioxidant systems. It has been implicated in multiple neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and ischemic stroke. Recently, emerging evidence has highlighted the role of ferroptosis in drug-induced pathological changes. Various types of abused substances including alcohol, cocaine, methamphetamine (METH) nicotine, cannabis, and opioids have been shown to disrupt ferroptosis-relevant pathways, leading to microglial activation and neuronal injury. Inhibition of ferroptosis could mitigate these pathological changes in preclinical models. Here, we summarize current evidence demonstrating the effects of abused drugs on ferroptosis pathways. Collectively, these findings underscore the potential role of ferroptosis in the pathophysiology of SUDs. Targeting ferroptosis may represent a promising therapeutic strategy for alleviating drug-induced neurological damage and improving recovery outcomes such as cognitive and memory deficiency in individuals with addiction.
1Introduction
SUDs represent a persistent global public health challenge, particularly in modern societies. Epidemiological studies estimate that more than 35 million individuals are affected by drug use disorders, frequently accompanied by neurological complications such as cognitive impairment, memory deficits, and behavioral abnormalities (Volkow and Blanco, 2023; Connery et al., 2020; Uhl et al., 2019). Among them, alcohol and opioid misuse are major contributors to morbidity and mortality (Sanchez-Roige et al., 2022). Beyond their health effects, SUDs exert profound societal impacts, including increased unemployment, crime, family instability, and homelessness, resulting in substantial economic burden (Daley, 2013). Despite decades of intensive basic and clinical research, the mechanisms underlying SUD pathogenesis remain incompletely understood. Notably, there are still no FDA-approved pharmacotherapies for certain addictions, such as cocaine use disorders (CUDs) (Schwartz et al., 2022). Therefore, identifying shared molecular pathways disrupted by different classes of abused drugs is essential for developing more effective therapeutic strategies.
Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, has recently emerged as a key mechanism linking iron dysregulation, oxidative stress, neuroinflammation, and neurodegeneration (Liu and Zeng, 2026; Christodoulou et al., 2026). Ferroptosis has been implicated in diverse pathological conditions, including viral infections, ischemic stroke, and neurodegenerative diseases (Wang L. et al., 2026; Zhang et al., 2026; Sun et al., 2026; Tao et al., 2026; Sandra Monserrat et al., 2026). Growing evidence indicates that various types of abused substances could interact with ferroptosis-related pathways, elevating ROS production, disrupting iron homeostasis, and impairing antioxidant defenses in the central nervous system (CNS) which contribute to microglial activation and neuronal injuries (Bo et al., 2023; Guo et al., 2022). Of note, pharmacological inhibition of ferroptosis alleviates neuroinflammatory responses and neuronal damages in multiple preclinical models (Khan et al., 2025). In this review, we summarize current evidence revealing how abused drugs modulate ferroptosis relevant pathways, with a focus on iron metabolism, ROS generation, lipid peroxidation, and antioxidant systems. Collectively, these findings suggest that ferroptosis may represent a convergent mechanism underlying drug-induced neurotoxicity and serves as a promising target for therapeutic intervention in SUDs.
2Overview of ferroptosis
2.1Ferroptosis pathways
Ferroptosis is a type of cell death process coordinately regulated by multiple signaling pathways. Since its formal description in 2012, ferroptosis has been increasingly acknowledged to play critical roles in various diseases including cancers, virus infection, stroke, and multiple neurodegenerative diseases (Wang L. et al., 2026; Zhang et al., 2026; Sun et al., 2026; Tao et al., 2026; Sandra Monserrat et al., 2026). Since there have already been excellent review papers discussing the complex mechanisms underlying ferroptosis regulation, we here just briefly outline the landmark events for ferroptosis discovery during the last three decades (Figure 1) and summarize the most well-known pathways critical for ferroptosis and deeply affected by abused drugs.
(1) Iron homeostasis: The cellular iron concentration is tightly regulated to keep balance due to its essential roles in metabolism with its potential toxicity (Muckenthaler et al., 2017). Iron is primarily imported into cells via transferrin receptor (TfR)-mediated endocytosis as Fe3+ status, which is subsequently reduced to Fe2+ and released into the cytosolic labile iron pool. Intracellular iron levels are mainly controlled through storage in ferritin in a non-reactive form, and export via ferroportin. Iron regulatory proteins (IRP1/2) are the key regulators of cellular iron balance, modulating the expression of TfR, ferritin, and ferroportin. Disruption of this regulatory network leads to intracellular iron accumulation, which can catalyze Fenton reactions to generate ROS and promote oxidative damage, thereby contributing to ferroptosis process.
(2) ROS production: ROS are highly reactive, oxygen-containing chemical molecules mainly including superoxide anion (), hydrogen peroxide (H2O2), hydroxyl radical (•OH), singlet oxygen, lipid hydroperoxides, and peroxynitrite (ONOO−). Several cellular origins of ROS have been identified. One major source is mitochondrial electron transport chain (ETC), where electron leakage during oxidative phosphorylation leads to formation (Shadel and Horvath, 2015). This is accompanied by the change in ultrastructural features of mitochondria which in ferroptosis exhibits smaller (shrunken) morphology with increased mitochondrial membrane density and reduced or absent cristae (Stockwell et al., 2017; Dixon et al., 2012). Another critical origin is membrane-associated NADPH oxidases which transfer electrons to oxygen. The third pathway involves iron-catalyzed reactions, particularly the Fenton reaction, in which ferrous iron (Fe2+) converts hydrogen peroxide into highly reactive hydroxyl radicals. Lipid metabolism also contributes to ROS generation through polyunsaturated fatty acid (PUFA) oxidation producing lipid hydroperoxides (Juan et al., 2021). Together, these pathways constitute a dynamic network for ROS production, when unchecked by antioxidant systems, promotes oxidative stress and drives ferroptosis.
(3) Lipid metabolism: Lipid metabolism is dynamically regulated by multiple pathways including the synthesis, influx and efflux, storage, and degradation which are essential for cellular membrane structure, energy balance, and signaling (Chandel, 2021). Phospholipids containing PUFAs are main components of cellular membranes determining membrane fluidity and susceptibility to oxidative damage. Inside cells, lipids can be stored as neutral lipids in lipid droplets or mobilized through lipolysis and β-oxidation to meet cellular energy demands. As mentioned above, lipid metabolism is closely linked to ROS production, and dysregulated lipid metabolism can promote lipid peroxidation and contribute to ferroptosis.
(4) Antioxidant pathways: Antioxidant system comprises a network of enzymatic and non-enzymatic defenses that maintain ROS homeostasis by neutralizing ROS and prevent oxidative damage (Huchzermeyer et al., 2022). Central to this system is glutathione (GSH), acting as a cofactor for glutathione peroxidase 4 (GPX4), reducing lipid hydroperoxides to non-toxic lipid alcohols and protects membrane integrity (Weaver and Skouta, 2022). Other key enzymatic antioxidants include superoxide dismutase (SODs), catalase, and peroxiredoxins, which convert superoxide and hydrogen peroxide into less reactive molecules. Non-enzymatic antioxidants such as vitamin E, coenzyme Q10 (CoQ10), and NADPH also contribute to maintaining ROS balance and regenerating antioxidant capacity (Manful et al., 2025). When these defense systems are compromised, such as during GSH depletion, GPX4 inactivation, or impaired NADPH supply, cells become vulnerable to excessive lipid peroxidation and oxidative stress, ultimately promoting ferroptosis.
3The effects of abused drugs on ferroptosis pathways
Emerging evidence suggests that ferroptosis acts as a bridge linking oxidative stress, neuroinflammation, and neuronal loss in multiple neurodegenerative diseases. Briefly, dysregulated iron homeostasis in the brain elevates the labile iron pool, promoting the Fenton reaction (ROS generation) that oxidizes PUFA-containing phospholipids, leading to irreversible membrane damage. This process is exacerbated by impaired antioxidant defenses. Ferroptosis interacts closely with neuroinflammatory pathways: damaged cells can release danger-associated molecular patterns (DAMPs), which activate microglia, increase the production of pro-inflammatory mediators, and further propagate oxidative stress, creating a self-reinforcing cycle of neuronal injury and inflammation. Previous investigations have shown that various types of abused drugs could interact with and affect iron metabolism, ROS production, lipid metabolism, and the antioxidant system. Therefore, it is highly possible that ferroptosis serves as a common mechanism underlying drug-induced neuroinflammation and neuronal injury although the hypothesis is still in embryo stage. Here, we summarize the effects of the six most common abused drugs on ferroptosis-relevant pathways, suggesting that targeting ferroptosis could be a novel therapeutic approach for mitigating neurological complications associated with SUDs.
4The potential therapeutic effects of ferroptosis inhibitors on SUDs and future directions
In this review, we collected evidence showing the profound effects of various types of abused drugs on ferroptosis pathways indicating this process might be the shared mechanisms responsible for abused drugs-mediated neuroinflammation and neuronal injuries. Based on numerous preclinical studies across multiple species, we propose a common pathological cascade induced by drugs of abuse. The initial event is disruption of the BBB, which facilitates peripheral iron influx and promotes cerebral iron overload. This is followed by excessive ROS production and lipid peroxidation, ultimately leading to collapse of the antioxidant defense system, particularly ferroptosis-associated pathways. Under conditions of chronic drug exposure, these three pathological processes, iron dyshomeostasis, oxidative stress, and antioxidant failure, may form a self-perpetuating vicious cycle that progressively amplifies microglial activation and chronic neuroinflammation. The resulting hostile neural microenvironment eventually leads to neuronal injury, synaptic dysfunction, and neurodegeneration, manifested as motor, cognitive, and memory impairments commonly observed in individuals with SUDs. At the same time, each drug exerts distinct effects on specific ferroptosis-related pathways, giving rise to both shared and drug-specific neuropathological alterations (Table 1).
| Substance | Primary Ferroptotic Mechanism | Key Brain Pathological Outcome |
|---|---|---|
| Alcohol (Ethanol) | Iron accumulation and GPX4 inactivation leading to ferroptotic death | Neuroinflammation, white matter degeneration, hippocampal neuronal loss, cognitive decline, increased susceptibility to neurodegeneration |
| Meth | Oxidative stress-driven ferroptosis through GPX4 depletion and lipid peroxidation | Dopaminergic neuron degeneration, striatal damage, cognitive impairment, memory deficits, increased risk of Parkinsonian pathology |
| Cocaine | Iron dyshomeostasis and oxidative stress promoting ferroptotic vulnerability | Basal ganglia iron accumulation, dopaminergic dysfunction, structural brain remodeling, cognitive deficits, enhanced neurodegenerative risk |
| Opioids (Morphine, Heroin, Fentanyl) | GPX4/GSH pathway suppression and ferroptotic activation | Neuroinflammation, microglial activation, impaired synaptic plasticity, opioid tolerance, cognitive dysfunction |
| Nicotine | Disruption of iron homeostasis with increased oxidative stress | Oxidative neuronal injury, cerebrovascular dysfunction, BBB disruption, increased vulnerability to neurodegenerative disorders (context-dependent) |
| Cannabis/Cannabinoids | Context-dependent modulation of ferroptosis and redox homeostasis | Altered synaptic signaling, cognitive impairment with chronic exposure, possible neuroprotection in some experimental models via antioxidant changes |
Therefore, therapeutic strategies aimed at interrupting this feed-forward pathological loop may provide a promising approach for alleviating the neurological abnormalities associated with chronic drug abuse. Indeed, pharmacological inhibition of ferroptosis has shown neuroprotective effects across multiple experimental models of SUDs (Summarized in Table 2). In addition, antioxidant compounds such as N-acetylcysteine, have been extensively reported to attenuate drug-induced neuronal injury, reduce oxidative damage, and preserve dopaminergic function (Smaga et al., 2021; Womersley et al., 2019). Of note, such treatments are mainly beneficial for neurotoxic damage and behavioral rigidity caused by long-term exposure with abused drugs. Whether targeting ferroptosis pathway could reduce the neuropsychological syndromes at the early phase of addiction cycle such as psychoactive effects and craving remain much unexplored until now. Also, current evidence remains largely restricted to in vitro and animal studies, and the clinical relevance of ferroptosis in human SUD pathology has yet to be firmly established. Future research should prioritize the development of brain-penetrant, selective ferroptosis inhibitors or inducers of endogenous defense systems (Figure 2), and evaluate their efficacy in reducing neurotoxicity, improving cognitive outcomes, and preventing relapse. Moreover, elucidating the interaction between ferroptosis and other forms of regulated cell death, as well as its role in withdrawal and relapse-related neuroadaptations, will be critical for advancing ferroptosis-targeted strategies as a novel adjunctive approach in the treatment of SUDs.
| Drug Class | Ferroptosis Inhibitor(s) | Primary Mechanism of Action | Supporting Preclinical Findings & Targets |
|---|---|---|---|
| Psychostimulants (Methamphetamine, Cocaine) | Liproxstatin-1 (Lip-1) (Hu et al., 2023) Ferrostatin-1 (Fer-1)(Hu et al., 2023; Lin et al., 2023) Deferiprone (DFP)(Hu et al., 2023) | Radical-trapping antioxidants (RTAs) iron chelation | •Attenuated neurodegeneration and oxidative neuronal injury •Restored NRF2–SLC7A11–GPX4 pathway •Reduced lipid peroxidation •Reduced intracellular Fe2+ |
| Alcohol (Ethanol) | Ferrostatin-1 (Fer-1)(Xu et al., 2022; Yu et al., 2026) | RTA | •Attenuated neuronal injury, •Restored GPX4 •Preserved synaptic proteins •Reduced lipid peroxidation |
| Opioids (Morphine) | Liproxstatin-1 (Lip-1)(Chen et al., 2019) Deferoxamine (DFO)(Huang et al., 2024) Cordycepin (Li et al., 2025) Naloxone (Huang et al., 2024) | RTA Iron chelation SIRT1 activation μ-opioid receptor antagonist | •Reduced lipid peroxidation •Restored antioxidant defenses •Reduces iron accumulation •Suppressed inflammatory cytokines |
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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