Authors: Hyung-Goo Kim (aDepartment of Neurosurgery, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway, NJ, United States), Mohammad Abdur Rashid (aDepartment of Neurosurgery, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway, NJ, United States), Michael Poleschuk (aDepartment of Neurosurgery, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway, NJ, United States), Faheem Ullah (aDepartment of Neurosurgery, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway, NJ, United States), Sang Hoon Lee (aDepartment of Neurosurgery, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway, NJ, United States), Sang Hoon Kim (aDepartment of Neurosurgery, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway, NJ, United States), Bo Qin (bCancer Prevention and Control Program, Rutgers Cancer Institute, New Brunswick, NJ, United States), X.F. Steven Zheng (cRutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, United States; dDepartment of Pharmacology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway, NJ, United States), Mi-Hyeon Jang (aDepartment of Neurosurgery, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway, NJ, United States)
Categories: Article, Chemobrain, Cognitive impairment, Chemotherapy, Neuroinflammation, Oxidative Stress
Source: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Authors: Hyung-Goo Kim, Mohammad Abdur Rashid, Michael Poleschuk, Faheem Ullah, Sang Hoon Lee, Sang Hoon Kim, Bo Qin, X.F. Steven Zheng, Mi-Hyeon Jang
Chemotherapy-induced cognitive impairment (CICI), commonly referred to as chemobrain, is a prevalent side effect of cancer treatment that severely affects survivors’ quality of life. Chemotherapeutic agents, including cisplatin, doxorubicin, and paclitaxel, cross the blood-brain barrier (BBB) and induce neurotoxicity, resulting in cognitive dysfunction. These agents trigger reactive oxygen species (ROS) generation, cause mitochondrial dysfunction, and induce DNA damage, all of which impair synaptic plasticity and neurogenesis. Mitochondrial dysfunction is central to chemobrain, as it disrupts ATP production, increases oxidative stress, and leads to neuronal apoptosis. Furthermore, mitochondrial DNA (mtDNA) damage caused by agents like cisplatin impairs oxidative phosphorylation, exacerbating neuronal degeneration. The molecular mechanisms of chemobrain likely involve several key players, including NAMPT-dependent NAD+ depletion and increased levels of Cyclooxygenase-2 (COX-2), which collectively exacerbate oxidative stress and neuroinflammation. Another important molecular target is the Adenosine A2A receptor (A2AR). When activated, it contributes to synaptic dysfunction and cognitive decline, particularly in chemotherapy-related cognitive deficits in the hippocampus. This review explores the complex interplay of these core pathologies in chemobrain and discusses how targeting these pathways could offer a therapeutic strategy to alleviate cognitive impairments in cancer survivors.
Chemobrain or chemotherapy-induced cognitive impairment (CICI) refers to a spectrum of cognitive deficits experienced by patients during and after chemotherapy. Risk factors include primary and metastatic tumors, as well as treatments like radiotherapy and chemotherapy, whether systemic or targeted. These cognitive symptoms, which affect a substantial number of oncology patients, can vary in severity and duration, with some individuals experiencing deficits years after completing treatment [1]. Recognized for its disruptive impact on survivors’ quality of life, chemobrain has gained increasing attention in the oncology community. Common symptoms include short-term memory deficits that hinder the ability to recall recent events or learn new information efficiently. Patients often report difficulties sustaining attention and impairments in executive functions, such as problem-solving, task organization, and planning [2]. These deficits can significantly affect professional performance and social interactions, which require mental quickness and emotional responsiveness, and they contribute to a sense of isolation when healthcare providers fail to adequately address patients’ concerns about cognitive decline. Emotional strain often exacerbates these cognitive difficulties, highlighting the urgent need for improved recognition and management strategies within healthcare settings.
Mechanistically, chemobrain shares biological underpinnings with other neurological disorders (Fig. 1). In particular, dysregulation of calcium signaling, essential for neuronal function and survival, has been implicated in chemobrain and neurodegenerative conditions like Alzheimer’s disease. In Alzheimer’s disease, calcium dyshomeostasis is associated with neurodegenerative processes [3]. Similarly, dysregulation of calcium signaling through the inositol 1,4,5-trisphosphate receptor (InsP3R) pathway and impaired neuronal morphology have been identified as mechanisms for paclitaxel-induced chemobrain [4]. Oxidative stress, in conjunction with inflammation, is also implicated in both chemobrain and neurodegenerative disorders (Fig. 1B, C). Elevated levels of pro-inflammatory cytokines, including TNF-α and IL-6, are observed in both conditions, suggesting a crucial role for inflammation in their development.
Chemobrain is often described as a form of “accelerated aging”, or premature neurodegeneration triggered by cancer treatment. While the molecular pathways may converge, chemobrain often presents with a more acute or subacute onset of cognitive symptoms during or shortly after treatment, which can nevertheless persist long-term.
This condition arises from the complex interplay of DNA damage, oxidative stress, mitochondrial dysfunction, and inflammation. These factors, often triggered by chemotherapeutic agents, disrupt critical cellular processes in the brain, including neuronal repair, energy metabolism, and synaptic plasticity. The resulting cognitive deficits, such as memory loss and impaired executive function, underscore the need for a comprehensive understanding of the underlying molecular mechanisms. Chemobrain may engage molecular pathways also implicated in neurodegenerative disorders. Reported processes include disrupted NAD^+^ metabolism, mitochondrial dysfunction, and persistent inflammatory responses following exposure to chemotherapy drugs. These mechanisms, amplified by chemotherapy-induced reactive oxygen species and cytokine-driven neuroinflammation, are thought to underlie the progression of chemobrain and highlight potential therapeutic targets. Such overlaps with neurodegenerative conditions underscore the complex interplay of molecular and genetic factors and point to promising directions for future research (Fig. 1).
Chemobrain is a well-recognized complication of cancer treatment that can arise during therapy and persist long after treatment completion. Estimates of how commonly it occurs vary widely across studies because of differences in patient populations, chemotherapy regimens, timing of assessment, and whether studies use patient-reported complaints or objective neuropsychological testing. Major reviews and clinical summaries emphasize this heterogeneity in prevalence estimates [1,5,6].
Most epidemiologic work has focused on adults treated for non-CNS cancers, particularly breast cancer, but chemobrain has been reported across tumor types and age groups. Survivors frequently report problems with memory, attention/concentration, processing speed and executive functions that affect daily functioning and work performance. Qualitative work highlights the substantial impact on employment, social roles and quality of life [2,6,7].
The course and timing of symptoms vary widely. Some patients report acute declines during chemotherapy, others develop symptoms in the months after treatment, and a subset shows persistent deficits for years, consistent with the concept of treatment-associated accelerated brain aging. Longitudinal cohort and review studies stress that persistence of deficits is more likely in those with lower baseline cognitive reserve and in the presence of other risk factors [1,5–7].
Risk factors identified in the literature include patient factors (older age, lower educational attainment/cognitive reserve), treatment factors (specific neurotoxic agents and cumulative exposure), and genetic susceptibility. Several papers discuss APOE4 (Apolipoprotein E variant 4), ALDH2 (Aldehyde dehydrogenase 2), COMT (Catechol-O-methyltransferase), and other genetic variants associated with increased vulnerability. Childhood ALL (Acute Lymphoblastic Leukemia) survivors are a distinct high-risk group for long-term cognitive sequelae after CNS-sparing systemic chemotherapy, with genetic and treatment-dose factors further modifying risk [8–12].
Susceptibility to chemobrain is significantly influenced by factors such as age, sex, and hormonal status. Older age itself increases vulnerability to chemobrain, as aging brains may have reduced cognitive reserve and heightened sensitivity to neurotoxic insults from chemotherapy [5]. Moreover, older breast cancer survivors with the COMT Val genotype are more likely to develop cognitive impairment during chemotherapy [13]. Additionally, chemotherapy agents can accelerate biological aging processes, further compounding brain changes and memory dysfunction similar to those seen in neurodegenerative conditions [14]. In aged mice, cisplatin treatment reduces synaptic proteins such as PSD-95 and induces abnormal Tau phosphorylation and aggregation, contributing to cognitive impairments with some parallels to Alzheimer’s-related neurodegeneration [15]. Sex may affect susceptibility to chemotherapy-related cognitive impairment, with some evidence that females, especially breast cancer patients, experience more frequent and severe symptoms [6]. However, data is limited and further research is needed. For instance, neuroprotective effects of nicotinamide mononucleotide (NMN) cisplatin-induced chemobrain have been demonstrated only in female mice, leaving male response uncertain [16]. Hormonal status may modulate susceptibility to chemobrain, particularly in estrogen-sensitive cancers like breast cancer, where estrogen depletion can impact cognitive function [6].
A consistent theme in epidemiologic studies is the gap between subjective complaints and objective test results. Many patients report cognitive difficulties that are not always captured on standardized neuropsychological batteries. Conversely, even patients who do not report noticeable cognitive difficulties may still show measurable decline on objective neuropsychological testing. This discrepancy has implications for study design (choice of endpoints) and for clinical screening and management [2,5,6].
Chemobrain is common but inconsistently documented. Prevalence and duration depend heavily on study methods and population. High-quality longitudinal studies with sensitive cognitive end-points and careful control for baseline risk factors are still needed to define precise incidence and long-term burden across tumor types and regimens [1,5–7]
Chemobrain arises from converging processes—DNA damage with maladaptive repair, mitochondrial dysfunction and oxidative stress, and neuroinflammation—that together impair synaptic plasticity, neurogenesis, and network integrity. Central nodes include nicotinamide phosphoribosyltransferase (NAMPT)-dependent NAD+ depletion and parthanatos, adenosine receptor signaling (A2AR/A3AR), COX-2/PGE2 pathways, and dysregulated Wnt3a/GSK3β/β-catenin signaling. Age- and genotype-linked susceptibilities (e.g., APOE4, ALDH2, COMT) further modulate risk. This framework motivates mechanism-aligned interventions aimed at restoring redox balance, mitochondrial function, and neuroimmune homeostasis. Emerging AI methods integrate multimodal neuroimaging with inflammatory and genetic markers to derive interpretable biomarkers and risk models that stratify patients and track disease trajectories.
Understanding DNA damage and repair mechanisms is essential when studying diseases like cancer and their treatment effects. DNA can be damaged by both endogenous sources, such as oxidative stress and metabolic byproducts, and exogenous sources, including UV light, ionizing radiation, and chemotherapeutic agents. If not properly repaired, this damage can lead to mutations, genomic instability, or uncontrolled cell growth, all hallmarks of cancer. Chemotherapy often works by inducing severe DNA damage to disrupt the rapid proliferation of cancer cells. While effective, this strategy frequently results in resistance to treatment and long-term effects, such as chemobrain, complicating therapeutic outcomes [17].
Chemotherapeutic agents induce DNA damage through various mechanisms. For example, topoisomerase inhibitors create single-strand breaks (SSBs) and double-strand breaks (DSBs) by obstructing DNA replication, while drugs like cyclophosphamide and cisplatin produce interstrand crosslinks (ICLs), preventing strand separation and inhibiting transcription and replication [18]. Alkylating agents introduce base alterations by adding alkyl groups to DNA, leading to mutations. To counteract these threats, cells rely on a network of repair mechanisms collectively known as the DNA damage response (DDR), which includes pathways such as base excision repair (BER) and nucleotide excision repair (NER), as well as signal transduction, cell-cycle checkpoints, and apoptosis induction (Fig. 1A).
Failure in DDR can lead to oncogene activation, tumor suppressor gene inactivation, and the development of cancer. Additionally, defects in DNA repair systems are linked to aging-related neurodegeneration and cognitive impairments. For instance, patients with genetic predispositions to reduced BER efficiency are more vulnerable to chemobrain. Enzymes such as 8-oxoguanine glycosylase (OGG1), which removes oxidative lesions like 8-oxoguanine (8-oxoG), and APEX1, which repairs apurinic/apyrimidinic (AP) sites, play critical roles in protecting neuronal integrity under oxidative stress. Reduced activity of OGG1 and APEX1 is associated with neurodegenerative conditions like Alzheimer’s disease and is exacerbated during chemotherapy, contributing to chemobrain [19].
NER, which addresses bulky helix-distorting DNA lesions like those caused by cisplatin, is another critical repair pathway. Patients with reduced NER efficiency are at higher risk of cognitive dysfunction following cancer treatment. Proteins such as XPC, XPA, and ERCC1-XPF, involved in NER’s damage recognition, verification, and excision steps, are essential for mitigating chemotherapy-induced DNA damage. Deficiencies in these proteins exacerbate neuronal cell death and contribute to the progression of neurodegenerative diseases like Alzheimer’s and Parkinson’s [20]. With age, NER activity declines, increasing susceptibility to neurodegeneration and paralleling the mechanisms underlying chemobrain.
Another mechanism linking chemotherapy to cognitive impairments is telomere shortening. Telomeres, which shorten naturally with each cell division, are critical for maintaining genomic stability. Excessive shortening caused by chemotherapy accelerates cellular senescence and apoptosis, particularly in non-target glial cells, thereby mimicking the aging process. This phenomenon has been linked to cancer susceptibility, Alzheimer’s severity, and increased mortality in older adults [21]. While cancer cells often evade senescence by upregulating telomerase activity, chemotherapy targeting this enzyme can inadvertently damage normal cells, contributing to cognitive deficits [22].
The interplay between genetic predispositions for DDR deficiencies and the additional DNA damage caused by chemotherapy significantly increases the risk of cognitive impairments. This persistent neuronal damage, compounded by age-related declines in repair efficiency, underscores the need for targeted strategies to protect cognitive function during cancer treatment.
Mitochondria are essential for neuronal health, supplying adenosine triphosphate (ATP) for brain energy metabolism [23], regulating calcium homeostasis, and mediating apoptotic pathways critical for cellular survival and function. As the powerhouse of the cell, mitochondria play a pivotal role in maintaining neuronal integrity by supporting synaptic activity, plasticity, and neurogenesis, all of which are fundamental for cognitive functions such as learning and memory. Dysfunctional mitochondria are characterized by impaired oxidative phosphorylation, leading to reduced ATP production and an increase in reactive oxygen species (ROS) generation, which causes oxidative stress [23]. This oxidative stress damages cellular components, including lipids, proteins, and DNA, and activates pro-apoptotic signaling pathways through the release of cytochrome c, contributing to neurodegenerative diseases such as Parkinson’s and Alzheimer’s diseases [24] (Fig. 1B).
Mitochondrial dysfunction is closely linked to disruptions in calcium homeostasis, which is critical for synaptic function and neuronal excitability [25]. Mitochondria act as buffers for calcium ions (Ca2 +), modulating intracellular Ca2 + concentrations to prevent excitotoxicity and maintain neuronal health. Dysregulation of calcium signaling due to mitochondrial impairment can lead to synaptic failure and neurodegeneration, ultimately affecting cognitive performance [26].
ATP production in neurons occurs via glycolysis and oxidative phosphorylation, with mitochondria being significantly more efficient, generating over 30 ATP molecules per glucose molecule compared to just two from glycolysis [27]. This high-energy demand underscores the brain’s reliance on mitochondrial function, especially for processes like synaptic activity, maintenance of ion gradients, and plasticity mechanisms underlying cognitive functions.
In addition to energy production, mitochondria are integral to neurodevelopment, influencing the growth of axons and dendrites, synapse formation, and programmed cell death (apoptosis) during neuronal differentiation [28]. Changes in mitochondrial metabolism are evident during brain development, with a metabolic shift from fatty acid oxidation in early stages to glucose utilization in mature neurons, reflecting the evolving energy requirements of proliferative neural stem cells versus differentiated neurons.
Mitochondrial dynamics, encompassing the processes of fission and fusion, are critical for maintaining mitochondrial quality control, distributing mitochondria within neurons, and supporting synaptic plasticity [29]. Dysregulation of these dynamics is associated with cognitive deficits, as impaired mitochondrial fusion and excessive fission can lead to fragmented mitochondria, reduced ATP production, and increased susceptibility to apoptosis [30].
Mitochondrial dysfunction is a key mechanism underlying chemobrain, with chemotherapeutic agents like cisplatin causing mitochondrial DNA (mtDNA) damage, reducing mitochondrial membrane potential, impairing ATP synthesis, and increasing ROS production (Fig. 1B). Cisplatin crosses the blood-brain barrier, forms adducts with mtDNA, disrupts protein synthesis, and induces oxidative stress, exacerbating neuronal damage. This mitochondrial toxicity impairs neural stem cell proliferation, dendritic outgrowth, and synaptic integrity, contributing to cognitive decline.
Additionally, chemotherapy-induced oxidative stress exacerbates damage by promoting lipid peroxidation, protein oxidation, and DNA damage, further impairing mitochondrial function and neuronal health (Fig. 1C). This oxidative stress and mitochondrial dysfunction are also central to the pathogenesis of various neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases [23]. Excessive production of ROS, coupled with impaired antioxidant defenses, disrupts electron transport chain function and activates apoptotic pathways, contributing to neuronal degeneration and cognitive impairment [31].
Therapeutic strategies targeting mitochondrial function offer promising avenues for mitigating chemobrain and neurodegenerative cognitive decline. Modulating mitochondrial dynamics to enhance fusion processes and maintain mitochondrial integrity can improve neuronal resilience [32].
Mitochondrial biogenesis is regulated by the PGC-1α signaling network, which plays a crucial role in maintaining mitochondrial function and cellular energy metabolism. Activating PGC-1α can enhance mitochondrial capacity [33], potentially contributing to improved cognitive outcomes.
In addition to mitochondrial-targeted compounds, antioxidant therapies such as N-acetylcysteine (NAC) have demonstrated potential in protecting neuronal mitochondria [34]. NAC serves as a precursor to cysteine, facilitating the synthesis of glutathione (GSH), a critical intracellular antioxidant that neutralizes reactive oxygen species (ROS) and maintains redox homeostasis [35]. By replenishing glutathione stores, NAC reduces oxidative stress within neurons, thereby mitigating mitochondrial damage, preserving mitochondrial membrane potential, and supporting ATP production.
In conclusion, mitochondria play a central role in neuronal function, development, and plasticity, with their dysfunction contributing to cognitive impairment through disrupted energy metabolism, calcium dysregulation, oxidative stress, and neuroinflammation. Understanding the intricate relationship between mitochondrial health and cognitive function provides a foundation for developing targeted therapeutic strategies to prevent and treat cognitive impairments associated with chemotherapy and neurodegenerative diseases.
Reactive Oxygen Species (ROS) are highly reactive, unstable oxygen derivatives containing unpaired electrons, primarily generated as byproducts of metabolism. Their excessive accumulation leads to oxidative stress, an imbalance with the body’s antioxidant defenses, ultimately causing damage to cells and tissues. Key ROS include hydrogen peroxide (H2O2), superoxide anion (O2^−^), hydroxyl radical (OH), and singlet oxygen (^1^O2), which act as second messengers in both normal and cancerous cells (Fig. 1C). ROS can promote or suppress tumors, depending on their regulation [36]. Cells control ROS levels through antioxidant enzymes like glutathione (GSH) and thioredoxin (Txn). Many chemotherapeutic agents induce ROS to drive cancer cell death. However, prolonged treatment may reduce ROS in cancer cells, contributing to drug resistance [36].
Mitochondria are the primary source of cellular ROS, with the electron transport chain (ETC) playing a key role. Under aerobic conditions, mitochondria generate ATP via oxidative phosphorylation, but deficiencies increase superoxide anion (O2^−^), leading to mitochondrial ROS (mtROS) accumulation. This excess ROS damages mitochondrial DNA (mtDNA), a key factor in the “mitochondrial theory of aging”. ETC complexes I and III are major ROS producers, with Complex I (NADH-ubiquinone oxidoreductase) being particularly susceptible to exogenous stressors like hypoxia. Complex III (ubiquinol-cytochrome c oxidoreductase) generates ROS during the Q cycle, with overproduction linked to genetic defects or chemotherapy exposure. Mitochondrial damage disrupts ETC function, reducing ATP production and increasing ROS accumulation (Fig. 1B). Uncoupling proteins (UCPs) including UCP2 and UCP3 protect against oxidative damage by dissipating the proton gradient, reducing ROS. Inflammatory cytokines, particularly TNF-α, further elevate ROS levels and impair Complex I activity, exacerbating mitochondrial dysfunction and ultimately triggering cell death. As mtDNA mutations accumulate, cells become more vulnerable to inflammation, triggering further ROS production. Damaged mitochondria also release pro-apoptotic factors like cytochrome C, accelerating aging and neurodegeneration [37].
Cancer cells exhibit higher ROS levels than normal cells due to metabolic reprogramming, genomic instability, mitochondrial dysfunction, and tumor microenvironment changes. To survive oxidative stress, they upregulate antioxidant defenses, particularly through NADPH-producing pathways like the pentose phosphate pathway (PPP) and AMPK activation during metastasis. ROS-mediated signaling supports tumorigenesis by promoting gene fusion and microRNAs, such as microRNA-210, which aid cancer progression. Because cancer cells balance ROS levels to avoid apoptosis, they are highly susceptible to therapies that elevate ROS beyond tolerable limits. Pro-oxidant therapies, including chemotherapy, increase intracellular ROS to trigger apoptosis and ferroptosis. However, cancer stem cells (CSCs) are resistant to oxidative stress, increasing the risk of metastasis and recurrence. Pro-oxidant therapies also pose toxicity risks, such as Fe^2+^ accumulation, leading to oxidative damage in healthy cells, particularly cardiomyocytes [38].
The brain and nervous system are highly vulnerable to oxidative stress due to the limited regenerative capacity of neuronal cells. Excessive ROS accumulation in the brain leads to oxidative damage, disrupting synaptic function and neuronal signaling, ultimately contributing to cognitive impairments known as chemobrain. Chemotherapy drugs, including doxorubicin and cyclophosphamide, have been shown to increase protein oxidation and lipid peroxidation in brain tissues, while platinum-based drugs like cisplatin and taxanes damage mitochondrial structures in ganglion cells, contributing to cognitive decline and peripheral neuropathy. ROS also compromise the blood-brain barrier (BBB), allowing oxidative damage to spread beyond the central nervous system (Fig. 1C). Chronic oxidative stress in the brain is a major contributor to long-term cognitive impairment in cancer survivors [38].
Neuroinflammation has emerged as a central mechanism underlying chemotherapy-induced cognitive impairment. Systemic administration of chemotherapy triggers the release of proinflammatory cytokines such as IL-1β, IL-6, and TNF-α, which can cross the blood–brain barrier and disrupt neural homeostasis [39]. Sustained neuroinflammatory responses impair synaptic plasticity, alter neurotransmitter balance, and damage white matter integrity, ultimately leading to deficits in memory, attention, and executive function. Moreover, chronic inflammation amplifies oxidative stress and mitochondrial dysfunction, accelerating processes that resemble neurodegeneration [40]. Elucidating the role of neuroinflammation in chemobrain is therefore critical, as it highlights a promising therapeutic target for mitigating cognitive decline in cancer survivors [41].
Among the inflammatory mediators implicated, cyclooxygenase-2 (COX-2) has gained particular attention as a downstream effector of cytokine signaling. COX-2, an enzyme responsible for producing prostaglandin E2 (PGE2), is upregulated by inflammatory signals in the brain, particularly in response to chemotherapy. Chemotherapy-induced stress promotes the release of pro-inflammatory cytokines like TNF-α and IL-6, which can cross the blood-brain barrier (BBB) and stimulate glial cells in the brain to produce additional inflammatory mediators. This cascade of events further amplifies COX-2 expression, contributing to neuroinflammation. The resulting inflammation damages neurons and leads to cognitive deficits [42].
Additionally, ROS generated during chemotherapy can activate the JNK pathway, further amplifying inflammation and neuronal damage by upregulating PARP1 and NF-κB expression. The selective COX-2 inhibitor NS398 has shown promise in preventing cisplatin-induced cognitive and mitochondrial impairments, highlighting COX-2’s role in chemobrain [42]. These findings suggest that targeting COX-2 and its downstream pathways may represent a viable strategy to alleviate chemotherapy-related neurotoxicity. Future studies integrating COX-2 inhibition with other anti-inflammatory approaches could provide synergistic benefits in preserving cognitive function among cancer survivors.
PARP1 is a nuclear enzyme integral to the DNA damage response (DDR), serving as a DNA damage sensor and mediator of repair mechanisms. Genotoxic stresses threaten cellular integrity by causing DNA damage, necessitating robust detection and repair pathways such as single-strand break repair (SSBR), base excision repair (BER), and double-strand break (DSB) repair via homologous recombination (HR) or non-homologous end joining (NHEJ) [43,44]. Upon DNA damage, PARP1 binds to break sites [45], catalyzing auto-ADP-ribosylation and recruiting repair proteins to maintain genomic stability [46,47]. Beyond DDR, PARP1 is activated in response to cellular stress, including unfolded protein response (UPR), stress granule formation, and pathogenic infections [48].
Critically, PARP1 is a major consumer of NAD+ , a cofactor central to brain aging and neurodegenerative disorders [49]. Hyperactivation of PARP1 can deplete NAD+ and ATP, triggering a regulated cell death pathway known as parthanatos. This cascade involves the accumulation of ADP-ribose polymers, mitochondrial AIF release, and massive DNA fragmentation. Dysregulation of PARP1 and NAD+ metabolism has been implicated in neuronal death, cognitive impairment, and neurodegeneration [50]. PARP1 also interacts with proteins linked to aging and genome stability, such as WRN, p53, ATM, and DNA-PK [51,52].
PARP1 hyperactivation is a hallmark of neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). In AD, PARP1 activity exacerbates Aβ plaque deposition, Tau tangle formation, and oxidative stress, accelerating cognitive decline [53]. BBB leakage, mitochondrial dysfunction, and reduced NAD+ levels further compound these effects [54]. Similarly, in PD, excessive PARP1 activation drives parthanatos, amplifying α-synuclein pathology and neuronal loss [55].
Chemotherapeutic agents, often associated with DNA damage and oxidative stress, present a parallel in the context of cognitive dysfunction (Fig. 1). Cancer survivors, particularly pediatric patients, exhibit heightened markers of DNA damage such as 8-oxoG, correlating with long-term cognitive deficits [56]. Clinically approved PARP inhibitors, such as olaparib, niraparib, and rucaparib, used for treating breast, ovarian, and prostate cancers, are also being investigated in combination with DNA-damaging therapies to enhance efficacy [57]. While these inhibitors hold promise in oncology, their potential in mitigating PARP1-mediated cognitive dysfunction remains an area of active investigation.
The molecular mechanisms underlying chemobrain and other neurological disorders are complex and multifaceted, involving a network of interconnected pathways such as oxidative stress, inflammation, and disruptions in cellular metabolism. Key players in these processes include nicotinamide adenine dinucleotide (NAD+), cyclooxygenase-2 (COX-2), adenosine A2A receptor (A2AR), and nicotinamide mononucleotide (NMN). These factors contribute significantly to the development and exacerbation of cognitive impairment associated with chemotherapy and other neurological conditions.
PGE2 is reportedly increased in Alzheimer’s disease, demonstrating the critical nature of this pathway in neurodegeneration and aging-related cognition [58]. Because PGE2 is a downstream mediator of COX-2 activity, its elevation provides a mechanistic link between inflammatory signaling and neurodegenerative processes. This connection highlights how multiple inflammatory pathways converge to disrupt synaptic function and cognition. The Adenosine A2A receptor (A2AR), a receptor for neuromodulator adenosine, is also implicated in synaptic dysfunction and cognitive impairment. In Alzheimer’s disease models, early synaptic deficits have been associated with A2AR activation, suggesting its role in cognitive decline. Activation of A2AR increases synaptic dysfunction and memory deficits. Elevated adenosine levels in the brain, particularly during stress or cellular damage, can lead to the overactivation of A2A receptors. Mouse studies have shown that A2A receptor signaling drives cisplatin-mediated hippocampal neurotoxicity and cognitive defects, further linking A2AR to chemobrain [59].
Chemotherapy accelerates biological aging, and emerging evidence suggests that chemobrain shares mechanisms with brain aging, particularly related to NAD+ depletion, which triggers parthanatos, a form of programmed cell death. Chemotherapy has been shown to reduce the levels of NAMPT, an enzyme critical for NAD+ synthesis (Fig. 1D). Notably, sustained expression of NAMPT in adult-born neurons prevents cisplatin-induced impairments in spatial learning and memory in mice, emphasizing the importance of NAD+ and adult-born neurons in mitigating the effects of chemotherapy on cognitive function [16].
Aldehyde dehydrogenase 2 (ALDH2) plays a vital role in metabolizing toxic aldehydes, thereby reducing oxidative stress implicated in chemobrain. Recent research indicates that the ALDH2_rs671 (GG) genotype may identify breast cancer patients at higher risk for chemobrain, as these individuals exhibit more pronounced cognitive decline following chemotherapy [12]. ALDH2 is highly expressed in critical brain regions involved in cognition and emotion, including the cerebral cortex, hippocampus, and amygdala. Its role in regulating aldehyde levels within astrocytes—cells essential for maintaining neural function—suggests a direct mechanistic link to chemobrain, especially since aldehyde accumulation contributes to cognitive impairments observed in both chemotherapy and ethanol exposure [12].
The APOE4 allele, linked to Alzheimer’s disease, is a major genetic risk factor for chemobrain, particularly in older cancer patients, due to its impact on neurogenesis and neural maturation [11]. APOE4 has been shown to exacerbate hippocampal pathology, neuroinflammation, and microglial reactivity [60]. Catechol-O-methyltransferase (COMT) gene, particularly the Val^108/158^ Met locus, influences dopamine concentration in brain synapses and is associated with cognitive impairment [61]. Carriers of the Catechol-O-methyltransferase (COMT) Val allele (commonly associated with the Val/Val and Val/Met at rs4680) have been shown to be more vulnerable to cognitive deficits following chemotherapy [13], offering another genetic susceptibility factor. Breast cancer survivors carrying the COMT Val allele demonstrated reduced performance in domains such as attention, motor speed, and verbal fluency. Similarly, in childhood acute lymphoblastic leukemia survivors, polymorphisms in genes involved in oxidative stress including COMT were linked to poorer cognitive outcomes after treatment [10].
A study revealed an association of GSK-3β rs3107669 polymorphism with chemotherapy-associated retrospective memory deficits in breast cancer survivors, suggesting it as a feasible genetic risk factor [62].
In summary, the complex interplay of molecular mechanisms, including NAMPT-dependent NAD+ depletion, COX-2 upregulation, A2AR activation, and NMN metabolism, alongside genetic susceptibilities such as the APOE4 allele, ALDH2_rs671 GG genotype, COMT Val allele, and GSK-3β rs3107669 polymorphism, forms a multifaceted network contributing to chemobrain. Disruptions in these pathways underscore the critical need for targeted therapies to protect brain health during and after chemotherapy.
Chemobrain arises not from isolated molecular insults but from the synergistic interplay among DNA damage, oxidative stress, mitochondrial dysfunction, and neuroinflammation. These mechanisms form a self-reinforcing loop, amplifying neuronal injury and cognitive decline. DNA damage is often the initiating event, triggered by chemotherapeutic agents that form DNA adducts or strand breaks [18]. In response, overactivation of DNA repair enzymes such as PARP1 leads to NAD^+^ depletion, compromising cellular energy metabolism and weakening mitochondrial function [50].
Damaged mitochondria, in turn, produce excessive reactive oxygen species (ROS), exacerbating oxidative stress and further damaging nuclear and mitochondrial DNA. This oxidative environment also disrupts calcium homeostasis and impairs synaptic signaling, undermining cognitive processing. Simultaneously, ROS and damaged mitochondria activate glial cells, fueling neuroinflammation through elevated cytokines like TNF-α and IL-6 [63]. Chronic inflammation not only perpetuates mitochondrial dysfunction and ROS generation but also impairs neurogenesis and synaptic plasticity, particularly in hippocampal regions critical for memory.
Thus, these molecular mechanisms are tightly interwoven. DNA damage leads to mitochondrial dysfunction and oxidative stress. ROS amplify DNA lesions and inflammation and neuroinflammation sustains mitochondrial and genomic instability. Breaking this pathogenic cycle by targeting central elements, such as NAD^+^ metabolism or mitochondrial ROS, offers a strategic avenue for therapeutic intervention in chemobrain. Key mechanisms and their actionable targets are summarized in Table 1.
Machine learning applied to neuroimaging (resting-state fMRI and diffusion/structural MRI) can detect and stratify chemobrain by learning multivariate network and microstructural patterns that are not captured by univariate analyses. Deep three-dimensional convolutional models trained on voxelwise fMRI features have classified chemobrain versus controls and visualized contributory brain networks, supporting the face validity of learned biomarkers [70]. Across published studies, models that use connectome features and multimodal MRI show moderate-to-high diagnostic performance for chemobrain detection in breast-cancer cohorts [70].
Beyond imaging, multivariate models applied to cytokine panels have identified inflammatory signatures associated with objective cognitive performance up to ten years after chemotherapy, underscoring the value of multimodal approaches that combine biology with imaging [71].
Explainable AI methods such as Integrated Gradients and SHAP can attribute predictions to specific networks, tracts, or cytokines, which improves biological interpretability and clinical trust. Federated learning with harmonized preprocessing across centers will be important for building generalizable models and for enabling prospective validation prior to clinical deployment [72].
Across clinical and preclinical studies, platinum agents (e.g., cisplatin), anthracyclines (doxorubicin), antimetabolites (methotrexate, 5-fluorouracil), taxanes (paclitaxel), and multi-agent regimens (e.g., R-CHOP) are linked to deficits in attention, memory, and executive function. Mechanistically, these exposures drive mitochondrial depolarization, elevated ROS, white-matter and synaptic injury, blood–brain barrier vulnerability, and reduced hippocampal neurogenesis. Model systems spanning human cortical neurons, rodent behavior, and neuroimaging converge on a pattern of lasting network dysfunction after treatment.
Chemotherapy agents, including cisplatin, doxorubicin, paclitaxel, methotrexate, and others, are linked to cognitive impairment, a phenomenon known as chemotherapy-induced cognitive impairment (CICI) or chemobrain. These agents cross the blood-brain barrier (BBB) and induce neurotoxicity, which may lead to DNA damage, oxidative stress, mitochondrial dysfunction, and neuroinflammation (Fig. 1).
Cisplatin, a platinum-based chemotherapy used for cancers such as lung, testicular, and ovarian, can cross the BBB, causing DNA damage and mitochondrial dysfunction by forming adducts with mitochondrial DNA (mtDNA). This impairs mtDNA replication and gene transcription, resulting in oxidative stress and neuronal apoptosis [73–75]. Even at reduced doses, cisplatin can cause cognitive deficits by affecting synaptic plasticity and neuronal function [76]. Similarly, doxorubicin, commonly used for breast cancer, induces oxidative stress, DNA damage, and mitochondrial dysfunction, all of which contribute to cognitive changes. Doxorubicin disrupts neuronal viability by downregulating DNA repair proteins, leading to mitochondrial-mediated apoptosis [77].
Paclitaxel (Taxol^®^), a taxane chemotherapy agent, is known to cause cognitive impairments via necroptosis and synaptic dysfunction. It crosses the BBB and causes neurotoxicity through mechanisms such as oxidative stress and apoptosis, which have been linked to cognitive decline and emotional disturbances [78,79].
Methotrexate, used primarily in childhood cancers, has been shown to activate microglia, impair oligodendrocyte precursor cells, and hinder myelination, contributing to cognitive dysfunction [9,80]. Other agents, such as 5-fluorouracil (5-FU), vincristine, methotrexate, carmustine, and cytarabine and cyclophosphamide, also contribute to cognitive impairment by inducing similar mechanisms of neurotoxicity [76,81].
Chemotherapy-induced neurotoxicity impairs neuronal function by disrupting neurogenesis, dendritic arborization, synaptic plasticity, and neurotransmission. Chemotherapeutic agents like cisplatin, doxorubicin, and methotrexate generate reactive oxygen species (ROS), which cause DNA damage and mitochondrial dysfunction. Oxidative stress, in turn, leads to neuronal degeneration and cognitive decline [82,83]. DNA damage, particularly in neurons, plays a significant role in cognitive impairments as neurons lack efficient DNA repair systems [84](Fig. 1A).
Clinical studies have shown that chemotherapy, including regimens like R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone), can exacerbate cognitive dysfunction [85]. The loss of white matter integrity, especially in the frontal lobe, is commonly observed in breast cancer survivors treated with chemotherapy, suggesting that chemotherapeutic agents contribute to the loss of oligodendrocytes and demyelination [86,87]. Methotrexate and 5-FU have also been shown to affect hippocampal neurogenesis and dendritic arborization, impairing learning and memory functions [88,89].
In rodent models, exposure to 5-FU and paclitaxel led to deficits in spatial memory and neuronal function in the hippocampus, further supporting the link between chemotherapy and cognitive dysfunction. These studies also highlight the impact of chemotherapy on neuronal progenitor cells and glial cells, which are more susceptible to damage compared to cancer cells [90,91]. Furthermore, paclitaxel has been associated with neuroinflammation, particularly the activation of astrocytes, which may contribute to cognitive impairments [92].
Overall, chemotherapy agents cause cognitive dysfunction through a variety of mechanisms, including DNA damage, oxidative stress, mitochondrial dysfunction, and inflammation. These changes affect key brain regions, such as the hippocampus and frontal cortex, which are crucial for memory and cognitive function. Understanding these mechanisms is essential for developing strategies to mitigate the cognitive side effects of cancer treatment.
Emerging therapeutic strategies for chemobrain focus on multifaceted approaches that address the interconnected molecular mechanisms of cognitive impairment, and a summary of leading candidates, pathways, evidence level, model context, and cognitive outcomes is provided in Table 2. Promising strategies align closely with these mechanisms and include Nrf2 activation and antioxidant support, NAD^+^ restoration (e.g., the NMN/NAMPT axis), adenosine receptor modulation (A2AR antagonists and A3AR agonists), selective COX-2 inhibition, and pathway-specific approaches such as GSK3β inhibition and PTPRO upregulation via miR-25–3p. Several candidates (e.g., dimethyl fumarate and istradefylline) already have clinical use in other indications, underscoring translational potential, while agents such as berberine and empagliflozin expand the pipeline of targeted neuroprotection. Most evidence is preclinical, and prioritized mechanism-anchored trials are needed to establish efficacy and optimize dosing in cancer survivors.
A primary focus in the search for chemobrain interventions is the Nrf2 pathway. Nrf2, regulated by its inhibitor Keap1, is recognized as a master regulator of the cellular antioxidant defense system. Under basal conditions, Keap1 binds to Nrf2 and promotes its ubiquitination and degradation, keeping Nrf2 levels low. However, under oxidative stress, Nrf2 dissociates from Keap1, translocates to the nucleus, and binds to antioxidant response elements (AREs) in DNA, activating the transcription of genes involved in antioxidant defense, detoxification, and cellular repair. Chemotherapy-induced oxidative stress disrupts this regulatory mechanism, leading to reduced Nrf2 activity and diminished antioxidant defenses. Impaired Nrf2 function exacerbates oxidative damage, mitochondrial dysfunction, and inflammation, all of which contribute to cognitive decline. Restoring Nrf2 pathway, therefore, represents a promising therapeutic target for combating oxidative stress and neurotoxicity in chemobrain [93]. Several studies have explored pharmacological activation of Nrf2, and notably, agents such as dimethyl fumarate (DMF) [66], are already clinically approved for the treatment of other neurological conditions, highlighting the translational potential of this approach.
Complementing Nrf2 activation, N-acetylcysteine (NAC) offers direct antioxidant properties, helping prevent lipid peroxidation and protein oxidation within mitochondria, providing an indirect yet significant protective effect against chemotherapy-induced mitochondrial dysfunction. Additionally, NAC contributes to neuronal protection by replenishing intracellular glutathione stores and directly scavenging reactive oxygen species, thereby mitigating oxidative damage and supporting mitochondrial integrity.
NMN, a precursor to NAD+ , has emerged as a potential therapeutic agent that supports cellular energy and mitigates age-related diseases and cognitive decline [65]. By increasing NAD+ levels, NMN improves cellular energy metabolism, reduces oxidative stress, and diminishes neuroinflammation, which in turn protects neurons and enhances cognitive function. NAD+ synthesis involves the conversion of NAM (nicotinamide) into NMN through the action of NAMPT, and subsequently, NMNAT (nicotinamide mononucleotide adenylyltransferase) further converts NMN into NAD+ .
Mitochondria-targeted drugs, such as delocalized lipophilic cations like triphenylphosphonium (TPP+) and peptide-drug conjugates, facilitate the selective delivery of therapeutic agents to mitochondria, enhancing drug efficacy while minimizing systemic toxicity [94]. Natural compounds with mitochondrial-targeting properties, including mito-honokiol, mito-resveratrol, mito-quercetin, and mito-curcuminoids, exhibit potential neuroprotective effects by reducing oxidative stress, enhancing mitochondrial biogenesis, and improving mitochondrial function in preclinical studies, particularly in cancer and metabolic disorders [95]. These compounds modulate key signaling pathways involved in mitochondrial dynamics, apoptosis, and antioxidant defense, offering potential benefits for cognitive health.
Building on the role of purine-based molecules in cellular health, modulation of adenosine receptors also presents a significant therapeutic strategy. The A2AR antagonist KW-6002 (Istradefylline), FDA-approved for Parkinson’s disease, prevents cisplatin-induced impairments in cognition and neurogenesis without affecting tumor growth or cisplatin’s antitumor efficacy. It has been shown to restore synaptic plasticity and dendritic spine density, and improve cognitive function in other neurological models. Its antagonism also attenuated cisplatin-induced increases in cAMP, CREB, and ERK, linked to neurogenic improvements [59].
Similarly, A3 adenosine receptor (A3AR) agonists exert neuroprotective effects by attenuating neuroinflammation and oxidative stress, actions that indirectly help preserve mitochondrial function, contributing to neuronal survival and reduced neurotoxicity [96]. Recent research further highlights the A3AR agonist MRS5980’s remarkable capacity to both prevent and reverse cisplatin-induced cognitive impairment, sensorimotor deficits, and neuropathic pain in preclinical models. Mechanistically, MRS5980 mitigates brain mitochondrial damage and oxidative stress, and critically, by activating key repair pathways such as NOTCH1 signaling and chromatin modification [67]. This underscores the translational promise of targeting the A3AR pathway for neuroprotection.
Addressing neuroinflammation more broadly, our studies have identified a causative role for COX-2-mediated prostaglandin E2 (PGE2) signaling in the development of cisplatin-induced cognitive deficits. This highlights the therapeutic potential of selectively inhibiting COX-2. Specifically, the selective COX-2 inhibitor NS398 has demonstrated the ability to prevent cisplatin-induced mitochondrial dysfunction and neuronal morphogenesis impairments when studied in human cortical neurons [42].
Poly(ADP-ribose) polymerase inhibitors (PARPi) represent a groundbreaking class of anti-cancer therapies targeting solid tumors, especially those with deficiencies in homologous recombination (HR) repair pathways, such as BRCA1 and BRCA2 mutations [97,98]. These inhibitors exploit the critical role of the PARP family of nuclear enzymes in DNA damage repair, with PARP1 being central to SSBR [99]. PARP1 inhibitors block the catalytic activity of PARP1 and trap the enzyme at DNA lesions, disrupting cellular repair processes. This “PARP trapping” mechanism interferes with the repair of DNA damage at stalled replication forks, leading to cytotoxicity and synthetic lethality in rapidly dividing tumor cells with homologous recombination deficiencies [100].
The U.S. FDA (Food and Drug Administration) and EMA (European Medicines Agency) have approved four PARP inhibitors—olaparib, niraparib, rucaparib, and talazoparib—for treating BRCA-mutated breast, ovarian, prostate, and pancreatic cancers [101,102]. Clinical trials have shown significant efficacy, with olaparib improving progression-free survival (PFS) in platinum-sensitive ovarian cancer patients [103], niraparib demonstrating extended PFS in BRCA-mutated cohort [104], and rucaparib and talazoparib yielding promising results in objective response rates and survival outcomes [105,106].
Beyond oncology, PARP inhibitors show potential for neuroprotection, with preclinical studies indicating their ability to mitigate neuroinflammatory and neurodegenerative conditions. For example, PARPi reduced amyloid-beta aggregates and improved motor function in Alzheimer’s disease models [107] and prevented neuronal death in Parkinson’s disease by inhibiting parthanatos-mediated toxicity [55]. Additionally, veliparib attenuated cognitive and motor deficits in traumatic brain injury models by reducing neuroinflammation and neuronal death [108].
The neuroprotective effects of PARPi are attributed to their ability to reduce oxidative stress, inflammation, and mitochondrial dysfunction while preserving cellular NAD+ levels, addressing pathologies associated with conditions like chemobrain, a cognitive impairment linked to cancer therapy [7,109]. With their dual role in targeting dysfunctional DNA repair pathways in cancer and mitigating neurodegenerative processes, PARP inhibitors hold immense promise as versatile therapeutics in precision medicine, warranting continued research into their broader applications, safety profiles, and optimization for clinical use.
Other emerging targets include Protein Tyrosine Phosphatase Receptor Type O (PTPRO), which is highly expressed in the hippocampus, but declines with age. PTPRO plays a significant neuroprotective role in chemobrain. Interestingly, berberine (BBR) has been shown to upregulate hippocampal PTPRO by downregulating miR-25–3p, suggesting a novel regulatory mechanism and a promising therapeutic avenue [69].
The Wnt3a/GSK3β/β-catenin signaling pathway is also implicated in doxorubicin-induced chemobrain. Specifically, doxorubicin inhibits Wnt3a, leading to the activation of GSK3β, which contributes to memory impairment and neuronal damage. Importantly, the administration of a GSK3β inhibitor, such as sb216763, has been shown to ameliorate these cognitive and neuronal deficits, offering a potential therapeutic strategy [68].
Finally, empagliflozin (EMPA) is presented as a promising neuroprotective candidate against doxorubicin-induced chemobrain, demonstrating strong clinical potential. Its mechanisms involve modulating SIRT1, NF-κB, NLRP3, and oxidative stress pathways, as well as reducing miRNA-34a and lncRNA HOTAIR gene expression [110].
Chemobrain remains a significant clinical challenge for cancer survivors, with profound implications for quality of life and long-term health. Accumulating evidence indicates that its pathogenesis involves interconnected mechanisms,including oxidative stress, mitochondrial dysfunction, DNA damage, neuroinflammation, and dysregulated signaling pathways. These mechanisms collectively impair neuronal function, reduce neurogenesis, and accelerate cognitive decline.
Therapeutic strategies targeting these mechanisms—such as Nrf2 activators, NAD^+^ precursors, PARP inhibitors, adenosine receptor modulators (A2AR antagonists and A3AR agonists), selective COX-2 inhibitors, and emerging targets like PTPRO and Wnt3a/GSK3β/β-catenin signaling—have demonstrated promise in preclinical studies. Moreover, compounds such as dimethyl fumarate, berberine, and empagliflozin highlight the translational potential of repurposing clinically available drugs for chemobrain. Nonetheless, most findings remain limited to animal models, and robust clinical trials are urgently needed to validate efficacy, optimize dosing, and establish safety in cancer survivors.
Future directions should include integrative approaches that combine pharmacological and non-pharmacological interventions, such as cognitive training, lifestyle modification, and nutritional support, alongside targeted therapeutics. Additionally, identifying reliable biomarkers—including genetic variants such as APOE4, ALDH2, COMT, and GSK-3β polymorphisms—will be crucial for predicting susceptibility, monitoring progression, and personalizing treatments. For a compact overview of mechanisms and candidates, refer to Table 1 and Table 2, respectively.
In conclusion, advancing our understanding of the molecular underpinnings of chemobrain and translating this knowledge into targeted therapies, including PARP inhibition, adenosine receptor modulation, COX-2 inhibition, and PTPRO regulation, offers a promising path forward. By bridging preclinical insights with clinical applications, the field has the potential to significantly improve cognitive health and overall quality of life for cancer survivors.