Peptide Neuromodulation in Autism Spectrum Disorder: Targeting Neuroinflammation, Mitochondrial Dysfunction, and Synaptic Plasticity

Abstract

Autism Spectrum Disorder (ASD) is a complex and heterogeneous neurodevelopmental condition characterized by persistent deficits in social communication and restricted, repetitive behaviors. Affecting approximately 1 in 36 children in the United States, ASD arises from multifactorial interactions among genetic, epigenetic, and environmental factors. Disrupted synaptic development, excitatory/inhibitory imbalance, chronic neuroinflammation, and mitochondrial dysfunction are key neurobiological features underlying core symptoms. Despite increasing recognition of these mechanisms, no FDA-approved therapies currently target the root neurobiology of ASD, and treatment remains focused on symptom management. Peptides, short chains of amino acids with high specificity and low immunogenicity, can modulate molecular pathways involved in neurotransmission, immune regulation, and cellular metabolism. Peptide therapy has emerged as a promising biologically targeted approach for ASD. Several candidate peptides, including mitochondria-derived peptides (MDPs) have demonstrated preclinical efficacy in enhancing social behavior, reducing repetitive behaviors, and normalizing circadian and metabolic rhythms. Mechanistically, these peptides exert neuromodulatory effects on GABAergic and glutamatergic systems, attenuate microglial activation and pro-inflammatory cytokine release, and restore mitochondrial function by reducing oxidative stress and supporting ATP production. Unlike cell-based therapies, peptide therapeutics can cross the blood-brain barrier and act directly on molecular targets critical for neuroplasticity and neuronal homeostasis. Early-phase clinical trials suggest that peptide therapies may benefit individuals with ASD, particularly those with identifiable neuroimmune or metabolic subtypes. However, translational challenges remain, including optimizing dosing, delivery, and patient stratification. This review synthesizes the current scientific rationale, mechanisms of action, and emerging clinical evidence for peptide therapy in ASD. By bridging neurobiology with precision therapeutics, peptide-based neuromodulation represents a novel and promising strategy to address the unmet need for disease-modifying treatments in ASD.

Keywords:Therapeutic Peptide, Autism Spectrum Disorder, Mitochondrial Dysfunction, Synaptic Plasticity, Neuroinflammation

Background

Autism Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental condition defined by persistent deficits in social communication and interaction, along with restricted, repetitive patterns of behavior, interests, or activities. Symptoms typically emerge before the age of three years and span a wide range of severity and functional impact (spectrum), reflecting the underlying biological complexity of the disorder. ASD affects approximately 1 in 36 children in the United States and is more commonly diagnosed in males [1]. The etiology is multifactorial, involving intricate interactions between genetic, epigenetic, and environmental influences. Numerous genes associated with synaptic development, neuronal signaling, and immune function have been implicated [2]. In parallel, prenatal environmental factors, including (but not limited to) maternal immune activation, toxin exposure, and perinatal complications, contribute to risk, yet the degree and extent to which is not known. Neurobiologically, ASD has been associated with early brain overgrowth, altered connectivity, excitatory/inhibitory imbalance, and chronic neuroinflammation3. These changes are reflected in the spectrum of behavioral phenotypes such as sensory processing abnormalities, executive dysfunction, communication difficulties, and challenges in social reciprocity [1,3].

Current treatment strategies for ASD primarily focus on behavioral interventions and pharmacologic management of associated symptoms (e.g., anxiety, hyperactivity, irritability) [1]. However, there are no FDA-approved therapies targeting the core neurobiological mechanisms of ASD. This gap has prompted increasing interest in biologically targeted therapies that modulate underlying pathophysiological processes. One such emerging modality to mitigate ASD manifestations is peptide therapy, which involves the use of short-chain amino acid sequences designed to influence cellular signaling, immune modulation, neuroprotection, and metabolic function [4]./p>

Peptides have been investigated for their ability to impact social cognition, reduce neuroinflammation, and promote synaptic plasticity across multiple neurologic conditions. In preclinical studies and early-phase clinical trials, peptide-based therapies have shown potential to improve social engagement, reduce repetitive behaviors, and regulate circadian rhythms in individuals with ASD [5]. Mechanistically, these peptides may modulate neurotransmitter systems (e.g., GABA, glutamate, oxytocin), attenuate microglial activation, enhance mitochondrial efficiency, and restore neuronal homeostasis. Peptide therapies offer several advantages, including targeted action, low immunogenicity, and relatively favorable safety profiles; however, many remain in investigational stages. The purpose of this review is to provide an up-to-date synthesis of the scientific rationale, mechanisms of action, current clinical evidence, and future directions for peptide therapy as a treatment approach for ASD. By critically evaluating existing data, we aim to clarify the therapeutic promise of peptides in addressing core features of ASD, while highlighting key challenges and considerations for their clinical translation.

Peptide Therapy in ASD

Peptide therapy in ASD capitalizes on the capacity of biologically active amino acid sequences to modulate key cellular signaling pathways, offering a precision-based approach to addressing the complex neurobiology of autism. Unlike cell-based therapies, peptides act directly at the molecular level to influence receptor activity, immune responses, neuroinflammation, and synaptic function— processes that are increasingly implicated in ASD pathophysiology. At least three key mechanisms support the potential therapeutic utility of peptides in ASD: (1) neuromodulation, through interaction with central neurotransmitter systems such as oxytocin, vasopressin, and glutamate-GABA pathways, which are critical to social cognition and sensory integration; (2) immunoregulatory effects, including the attenuation of microglial activation and the normalization of pro-inflammatory cytokine profiles; and (3) metabolic and mitochondrial support, where select peptides enhance cellular energy metabolism and reduce oxidative stress, common features in subsets of individuals with ASD [6,7].

Neuromodulation via Peptide Therapy

The use of peptide therapy for neuromodulation involves leveraging bioactive peptides, particularly those derived from mitochondria and peripheral tissues, to regulate and restore neural function [8]. Therapeutic administration of peptides can influence key processes such as synaptic plasticity, neuroinflammation, and cell survival by modulating intracellular signaling, mitochondrial activity, and crosstalk between the central nervous system (CNS) and peripheral organs. Mitochondria-derived peptides (MDPs), (e.g., humanin, MOTS-c, and small humanin-like peptide 2 [SHLP2]), have demonstrated neuroprotective effects by enhancing mitochondrial resilience, reducing oxidative stress, and promoting neuronal survival [9]. In the context of ASD, neuromodulation offers a promising avenue for addressing the underlying neurobiological dysfunctions often observed in affected individuals.

Mitochondria, along with the nucleus, are the only organelles that harbor their own DNA. Human mitochondrial DNA (mtDNA) encodes 13 protein-coding genes and 24 RNA molecules essential for mitochondrial protein translation. Although the peptide repertoire encoded by mtDNA is small, it includes mitochondria-derived peptides (MDPs) which have demonstrated neuroprotective effects. The first MDP to be discovered was humanin, a 24–amino acid peptide encoded from the 16S rRNA region of mtDNA cloned from the resilient occipital lobe of an Alzheimer’s disease patient’s brain and found that the peptide protected against amyloid-β toxicity in neuronal cells. Humanin was also shown to protect neurons from amyloid-beta and oxidative stress-induced apoptosis. Recently, Kim [10] showed a novel role of humanin administered intranasally to improve in mitochondrial function and neuronal survival in Parkinson’s disease. Similarly, MOTS-c, a peptide encoded by the short open reading frame of the mitochondrial 12S rRNA gene significantly expressed in response to stress or exercise and translocated to the nucleus, was shown to modulate inflammatory responses and metabolic signaling in glial cells [11]. Moreover, SHLP2, an MDP implicated in several biological processes such as aging and oxidative stress, was shown to support mitochondrial homeostasis and neuron survival under stress conditions [9].

The underlying mechanistic underpinnings of mitochondrial dysfunction, particularly in a subset of individuals with ASD, highlight the effect that deficits in energy metabolism has on impairment of neural development and connectivity [12]. As such, MDPs could potentially restore mitochondrial health and support energy- intensive processes like synaptogenesis and neurotransmission. The consequent neuroinflammation and immune dysregulation may be mitigated by mitochondrial peptides via influence on cytokine signaling and glial cell activity. It is plausible that abnormal synaptic signaling and plasticity, central to the behavioral and cognitive symptoms of ASD, could be modulated by peptides that enhance neuronal resilience and plasticity, thereby supporting improved communication between neural circuits [13]. Additionally, the fact that MDPs can cross the blood-brain barrier (BBB) makes them especially attractive as therapeutic candidates for systemic administration [14].

Mitochondria, along with the nucleus, are the only organelles that harbor their own DNA27. Human mitochondrial DNA (mtDNA) encodes 13 protein-coding genes and 24 RNA molecules essential for mitochondrial protein translation. Although the peptide repertoire encoded by mtDNA is small, it includes mitochondria-derived peptides (MDPs) which have demonstrated neuroprotective effects. The first MDP to be discovered was humanin, a 24–amino acid peptide encoded from the 16S rRNA region of mtDNA cloned from the resilient occipital lobe of an Alzheimer’s disease patient’s brain and found that the peptide protected against amyloid-β toxicity in neuronal cells. Humanin was also shown to protect neurons from amyloid-beta and oxidative stress-induced apoptosis. Recently, Kim showed a novel role of humanin administered intranasally to improve in mitochondrial function and neuronal survival in Parkinson’s disease. Similarly, MOTS-c, a peptide encoded by the short open reading frame of the mitochondrial 12S rRNA gene significantly expressed in response to stress or exercise and translocated to the nucleus, was shown to modulate inflammatory responses and metabolic signaling in glial cells. Moreover, small humanin-like peptide 2 (SHLP2), an MDP implicated in several biological processes such as aging and oxidative stress was shown to support mitochondrial homeostasis and neuron survival under stress conditions.

The advances in utilizing MDPs, such as humanin and MOTS-c, encoded within the mitochondrial genome, exert protective roles in neuronal systems and suggest that modulating mitochondrial signaling can be a viable therapeutic strategy. However, as our understanding of mitochondrial biology expands, a novel therapeutic frontier has emerged in nano organo peptides and mitochondrial organelle (MO) peptides. Unlike traditional MDPs, NOP and MO peptides encompass a broader class of peptides generated within or associated with the mitochondrial organelle, including those derived from mitochondrial protein processing, inter-organelle signaling interfaces, and stress-induced mitochondrial proteolysis. NOPs and Mito Organelles (MO) peptides have been extensively used in humans and animals.

NOPs are 3nm in size and have a molecular weight of less than 10kDA [3], procured from mammalian stem cells and are processed through a proprietary parallel-extraction process that includes multiple ultrafiltrate steps through specialized Millipore’s to obtain the cellular material within the cell, known as the molecular-level ultrafiltrates. Owing to the extraction process, these ultrafiltrates are specific to the cell type that they are derived from. NOP contents are extracted from organ specific cells with an initially high molecular mass and subsequently separated through various ultrafiltration steps through micro-Millipore filters. This selective filtration process only allows substances with a molecular mass of less than 10kDa to pass, thereby ensuring peptide specificity. Moreover, the small molecular weights and high solubility of NOPs permits their delivery via both sublingual and injectable routes (either subcutaneous or intramuscular) [15] NOPs have been investigated and utilized for a variety of applications including cosmetics and regenerative organ repair [15].

MO peptides are biologically extracted mixtures of cellular peptides that have predominantly mitochondria-specific functions [16]. Although cells of different organ systems have similar functions, variations in cellular functions between organs create the differential expression of peptides, which can be utilized for therapeutic purposes. As part of the aging process, the volume and strength of signals to the mitochondria declines, causing signals to be sent back to the nucleus to arrest cell proliferation and initiate apoptosis and cell death. MO peptides are organ-specific extracts that are aimed at revitalizing and rejuvenating mitochondrial activity, thereby regenerating cells and organisms. Unlike NOPs, MOs are larger in size and have predominantly mitochondria specific functions that allow for a more pronounced revitalization of mitochondrial function [16].

This expanded scope offers a new dimension for intervention, potentially allowing for more precise modulation of mitochondrial- synaptic crosstalk, regulation of mitophagy, and control of mitochondrial- mediated cell death pathways. Transitioning from MDPs to MOPs thus represents a shift from targeting general mitochondrial stress responses to harnessing the organelle’s full peptidome as a programmable interface for therapeutic control in ASD.

Immunoregulatory Effects of Peptide Therapy

Peptide-based therapies offer a promising avenue for immunoregulation by modulating inflammatory signaling pathways, restoring cytokine balance, and influencing immune cell activity [17,18]. Certain neuroactive peptides have been shown to inhibit the production of pro-inflammatory mediators, promote anti-inflammatory cascades, and regulate the function of T cells, B cells, and innate immune cells, including microglia [19]. Through these mechanisms, peptide therapy has the potential to rebalance immune homeostasis, thereby reducing neuroinflammation that impairs synaptic connectivity and contributes to behavioral dysregulation in ASD. In addition, peptides may support BBB integrity and mitigate oxidative stress, two physiological domains commonly disrupted in immune-mediated ASD phenotypes [6]. These immunomodulatory properties provide a compelling biological rationale for the use of peptide-based interventions in ASD subtypes characterized by inflammation and immune dysfunction. As with neuromodulation, MO peptides offer a unique therapeutic axis by directly targeting the intracellular organelle that integrates metabolic stress, immune signaling, and programmed cell death key pathways implicated in ASD pathophysiology. This paradigm shift expands the peptide- based toolkit beyond canonical MDPs, positioning mitochondrial organelle peptides as next-generation candidates for precision neuroimmune modulation in ASD.

Metabolic Homeostatic Reset with Peptide Therapy

The inextricable link among disturbances in mitochondrial function, redox balance, and cellular energy metabolism and impaired neuronal signaling, synaptic dysfunction, and altered neurodevelopment in ASD lends the potential for peptide-based therapies to restore of metabolic homeostasis by targeting key pathways involved in oxidative stress regulation, mitochondrial efficiency, and cellular repair [12,13]. Certain therapeutic peptides have been shown to enhance mitochondrial function, reduce reactive oxygen species (ROS), and promote antioxidant defense mechanisms, thereby supporting neuronal and glial resilience under metabolic stress [20-22]. Reactive oxygen species (ROS) and inflammation are critical contributors to aging and disease pathogenesis. Pro-inflammatory cytokines such as interleukin‐1 (IL‐1), IL‐4, IL‐10, and tumor necrosis factor alpha (TNFα) serve as upstream signals in these pathways. These inflammatory and oxidative insults can disrupt protein folding, interfere with post-translational modifications, and impair mitophagic processes. ROS-induced mitochondrial damage necessitates the activation of multiple molecular systems to restore cellular equilibrium. When mitophagy is compromised, cellular function declines, contributing to the onset of metabolic dysregulation. Therefore, restoring mitophagy capacity in aging cells presents a promising strategy to promote metabolic homeostasis. Additionally, peptides can modulate key signaling pathways such as AMPK and mTOR, which are critical regulators of energy balance and cellular homeostasis. In preclinical models, peptide interventions have demonstrated the capacity to correct metabolic dysfunction and improve neurobehavioral outcomes. By addressing bioenergetic impairments and oxidative stress, the core features in metabolically vulnerable ASD subtypes, peptide therapy offers a biologically grounded strategy for mitigating symptoms and promoting healthier neural development.

Non-clinical Studies

In an effort to identify a link between cellular immune dysregulation and ASD-related behavioral deficits Haiso, et al., [23] used a mouse model of autism. They found that offspring of immune-activated mothers display altered immune profiles and function, characterized by a systemic deficit in CD4(+) TCRβ(+) Foxp3(+) CD25(+) T regulatory cells, increased IL-6 and IL-17 production by CD4(+) T cells, and elevated levels of peripheral Gr-1(+) cells. Building on these findings, recent preclinical studies have further explored potential therapeutic strategies, including peptide-based treatments, to address the neurobiological abnormalities associated with ASD. Preclinical studies have provided growing support for the use of peptide-based therapies in the treatment of ASD, particularly by targeting key neurobiological abnormalities such as impaired social behavior, neuroinflammation, excitatory/inhibitory imbalance, and mitochondrial dysfunction [24-26]. Several classes of peptides have been investigated in animal models that exhibit core ASD-like features, including social deficits, repetitive behaviors, and altered neurochemical signaling. One of the most widely studied peptides is oxytocin, a neuropeptide known for its role in social bonding and affiliative behavior. In rodent models of ASD, such as valproic acid (VPA)-exposed or genetically modified mice, oxytocin administration (intranasally or peripherally) has been shown to improve social interactions, increase social novelty preference, and normalize amygdala activity and synaptic plasticity. These effects are thought to involve modulation of GABAergic signaling and rebalancing of excitatory/inhibitory neurotransmission [27,28]. Vasopressin receptor agonists and antagonists have also been explored for their influence on social cognition and anxiety-related behaviors. In particular, V1a receptor antagonists have been shown to enhance social communication in rodent ASD models [24,25]. Neuroprotective peptides, such as NAP (davunetide), derived from activity-dependent neuroprotective protein (ADNP) have demonstrated efficacy in ASD models by stabilizing microtubules, improving mitochondrial function, and enhancing synaptic plasticity. NAP treatment has been shown to reduce oxidative stress and improve cognitive and behavioral outcomes in models of neurodevelopmental delay [26]. Additionally, synthetic antioxidant peptides and anti-inflammatory peptides have been used to attenuate neuroinflammation and oxidative damage in ASD models. These peptides reduce pro-inflammatory cytokines such as TNF-α and IL-6 and restore redox balance, leading to improved behavioral profiles [29]. Collectively, these preclinical findings highlight the promise of peptide-based interventions in ASD by demonstrating their ability to modulate core pathophysiological processes while maintaining favorable safety profiles. Nonetheless, clinical translation remains early, and further research is needed to optimize delivery methods, dosing strategies, and patient stratification for maximal therapeutic benefit.

We16 conducted a study s to demonstrate metabolic restoration administering MO peptides twice-weekly to NOD mice through intramuscular injections over 17 weeks delays or prevents the onset of the destruction of the insulin-secreting beta cells in pancreatic islets of Langerhans. Specifically, the stem-cell derived MO peptides were obtained from thymus and pancreatic extracts to target the regions of the beta cells and T-cell maturation [16].

A cytokine panel consisting of 45 cytokine assays was obtained using serum samples of each mouse. A significant difference in the concentration of Erythropoietin (EPO) and Chemokine Ligand 5 (CCL5), otherwise known as RANTES, was found between MO peptide mice and control mice. NOD MO peptide mice had an average EPO concentration of 374.88pg/mL while the NOD saline mice had an average EPO concentration of 203.68pg/mL (p = 0.0062) in the MO peptide treated group compared to sham controls. NOD MO peptide mice had an average CCL5 concentration of 14.37pg/ mL while the NOD saline mice had an average EPO concentration of 8.08pg/mL (p = 0.031). The study provides important preliminary data that suggests that MO peptides may assist in delaying the onset or preventing T1D and represents an exciting therapeutic option to further investigate.

Clinical Studies

Clinical studies investigating peptide therapy for ASD have shown promising results in addressing various core symptoms. Oxytocin, a neuropeptide, has been extensively studied for its potential to improve social behavior and communication skills in individuals with ASD. Studies such as Andari, et al., [30]. and Yatawara, et al., [31] demonstrated that intranasal oxytocin administration led to improvements in social cognition, emotion recognition, and social functioning in children with ASD, highlighting its therapeutic potential. Vasoactive intestinal peptide (VIP) has also garnered attention due to its role in modulating neuroinflammation and enhancing social behavior, and VIP may influence neurotransmission and reduce inflammation, making it a promising target for ASD treatment [32]. Additionally, research into peptides impacting the gut-brain axis [4], has identified gastrointestinal disturbances as common in individuals with ASD, paving the way for gut-brain peptides as a treatment avenue. Melatonin, a neuropeptide involved in sleep regulation, has been studied for its ability to alleviate sleep disturbances in ASD, with findings from Rossignol & Frye [33] suggesting that melatonin supplementation improves sleep and overall functioning. Finally, neuropeptides like neurotensin and neuropeptide Y (NPY) have been explored for their potential in addressing core ASD symptoms such as social deficits and repetitive behaviors [6]. These studies underscore the diverse ways in which peptides can target neurobiological abnormalities in ASD, from social behavior to gastrointestinal function.

While clinical studies with peptide therapies for ASD are still in early stages, there is promising evidence suggesting that peptides like oxytocin, melatonin, and VIP could provide therapeutic benefits in managing symptoms of ASD, particularly those related to social behavior, sleep disturbances, and neuroinflammation. Further research, including larger and more diverse clinical trials, will be essential to confirm their efficacy and safety for individuals with ASD. However, as the field continues to evolve and advanced therapeutic strategies evolve, new peptide-based therapies specifically targeting mitochondrial dysfunction and cellular bioenergetics offer novel therapeutic avenues for ASD.

Emerging evidence suggests that mitochondrial dysfunction, commonly observed in individuals with ASD, may contribute to neurodevelopmental and behavioral symptoms. NOPs and MO peptides could play a pivotal role in addressing these metabolic and energy deficits, offering targeted treatments to enhance mitochondrial function and restore cellular health. By focusing on the mitochondria’s role in neuroplasticity and neuroinflammation, these therapies have the potential to not only alleviate core symptoms but also improve overall cognitive and behavioral outcomes in ASD.

Discussion

e brain is an energetically demanding organ, utilizing roughly 20% of the body’s total caloric intake despite comprising only about 2% of total body weight. This high energy consumption is primarily driven by the need for ATP to sustain ionic gradients that are essential for effective neurotransmission and neural plasticity.

CNS peptides are critical in regulating emotional and social behaviors, in addition to supporting speech and cognitive development. The addition of MO peptides and neuropeptides after the transplantation of neuronal precursors has led to a significant reduction in anxiety and notable improvements in behavioral outcomes for individuals with ASD. A comprehensive approach for treating ASD, was introduced using advanced neuropeptides, growth factors, and tissue repair agents derived from fetal neural precursor stem cell cultures5. The neuropeptides, essential for managing higher brain functions, including reflexes (both conditioned and unconditioned), as well as complex cognitive processes that support appropriate behavior in diverse social and environmental situations, were developed. These innovative CNS peptides contribute to increased self-esteem, diminished aggression, and improved communication skills and social adaptability. Typically, after 4-6 months of therapy, patients exhibit improvements in conversation skills, a decrease in repetitive motor behaviors, and greater flexibility with routines. Additionally, clear advancements in higher cognitive functions, such as enhanced peer interactions, better social and emotional responses, and progress in speech development, verbal communication, and learning were observed.

Mitochondria are central to these processes, playing crucial roles in neural development and function, including the proliferation, differentiation, and maturation of neural stem cells. They also support the extension of dendrites and contribute significantly to both developmental and synaptic plasticity. Moreover, mitochondria are key regulators of cell survival and programmed cell death [5]. Peptides are intricately linked to neurodegenerative diseases (NDDs). Over the past decades, researchers have tirelessly pursued understanding the pathogenesis of NDDs through extensive basic studies and clinical trials targeting peptides for treatment. This endeavor has led to the development of several marketed peptide- based drugs. However, the complexity of neurodegenerative disease mechanisms remains beyond our current understanding. Further investigation is needed to elucidate their mechanisms of action, and scientists must explore novel formulations and delivery methods to optimize the functionality of peptides [34].

While peptides offer several advantages to traditional ASD treatment strategies with the ability to be administered systemically or intranasally without the need for genetic manipulation, are typically well-tolerated, and have low immunogenicity [5], key challenges remain, including determining the long-term safety of chronic peptide administration, understanding pharmacokinetics and tissue-specific activity, and identifying the most effective peptide candidates and dosing strategies. Uncertainties also persist regarding optimal timing of intervention, potential interactions with other treatments, and durability of therapeutic effects.

Analogous to how non-neural organs secrete neurotrophic factors, peripheral tissues, such as skeletal muscle, liver, and immune cells, release peptides and signaling molecules that influence CNS repair. Evidence from other organ systems suggests that a combination of mitochondria-derived (i.e. MOP) and tissue-specific peptides (i.e., NOPs), originating from muscle, endothelial, and hematopoietic cells, could be harnessed to support neuroregeneration. Neurons and glial cells are particularly dependent on mitochondrial function due to their high energy needs and limited regenerative potential. In both acute CNS injuries (e.g., stroke, spinal cord trauma) and chronic neurodegenerative diseases (e.g., Alzheimer’s, Parkinson’s), mitochondrial dysfunction emerges as a key pathological feature, resulting in increased oxidative stress, disrupted ATP production, and impaired intracellular signaling [34].

Given the unique nature of mitochondria, along with the nucleus, possessing their own DNA, human mitochondrial DNA (mtDNA) provides the opportunity for leveraging a family of MDPs with demonstrated neuroprotective properties [34,35]. The novel research on MO peptides in the context of ASD while still emerging, has garnered substantial interest translating the role of mitochondrial dysfunction in other neurodevelopmental disorders [33], supporting opportunitistic pathways to leverages therapeutic strategies in ASD. The critical aspects of mitochondria for cellular energy production and the widespread adverse consequences of dysfunction have been inextricably linked to several neurodevelopmental and neuropathological conditions applicable to ASD, were highlighted by Lee, et al., [36] demonstrating MO peptides regulate mitochondrial function and improve metabolic homeostasis. We have also previously highlighted the potential therapeutic effects of MO in the injured and aging brain [37] and the gastrointestinal tract, [38] linking the potential utility in neuromodulation and the gut-brain axis pathways of ASD.

In conclusion, MO peptides represents a promising frontier in the treatment of ASD, offering a targeted, biologically informed approach to address the underlying neuroimmune, synaptic, and metabolic disturbances that characterize the condition. By harnessing the therapeutic potential of mitochondria, ASD treatment strategies are moving beyond symptomatic management toward interventions that modulate core pathophysiological processes. NOPs and MO peptides offer unique advantages, including high specificity, favorable safety profiles, and the capacity to cross the BBB, making them well-suited for CNS-targeted therapies. While early findings are encouraging, the field remains in a formative stage, with critical questios surrounding optimal delivery methods, long-term efficacy, and patient stratification yet to be fully addressed. Continued translational research, guided by mechanistic insights and precision medicine frameworks, will be essential to realize the full therapeutic potential of NOPs and MO peptide interventions in ASD.

References

1. Hodges H, Fealko C and Soares N (2020) Autism spectrum disorder: definition, epidemiology, causes, and clinical evaluation. Transl Pediatr 9(Suppl 1): S55-S65.
2. Wiśniowiecka Kowalnik B and Nowakowska BA (2019) Genetics and epigenetics of autism spectrum disorder-current evidence in the field. J Appl Genet 60(1): 37-47.
3. Gao R and Penzes P (2015) Common mechanisms of excitatory and inhibitory imbalance in schizophrenia and autism spectrum disorders. Curr Mol Med 15(2): 146-167.
4. Puricelli C, Rolla R, Gigliotti L, Boggio E, Beltrami E, et al (2021) The Gut-Brain-Immune Axis in Autism Spectrum Disorders: A State-of-Art Report. Front Psychiatry 12: 755171.
5. Klokol D, Wong MBF and Chan MKS (2024) Advancements in autism: exploring innovative therapies and targeted approaches to management and reversal of neurodevelopmental disorders. J Neurol Stroke 14(5): 122-132.
6. Jiang CC, Lin LS, Long S, Ke XY, Fukunaga K, et al (2022) Signalling pathways in autism spectrum disorder: mechanisms and therapeutic implications. Signal Transduct Target Ther 7(1): 229.
7. Won H, Mah W and Kim E (2013) Autism spectrum disorder causes, mechanisms, and treatments: focus on neuronal synapses. Front Mol Neurosci 6: 19.
8. Miller B, Kim SJ, Kumagai H, Yen K and Cohen P (2022) Mitochondria-derived peptides in aging and healthspan. J Clin Invest 132(9): e158449.
9. Kim SJ, Xiao J, Wan J, Cohen P and Yen K (2017) Mitochondrially derived peptides as novel regulators of metabolism. J Physiol 595(21): 6613-6621.
10. Kim KH (2023) Intranasal delivery of mitochondrial protein humanin rescues cell death and promotes mitochondrial function in Parkinson’s disease. Theranostics 13(10): 3330-3345.
11. Wan W, Zhang L, Lin Y, Rao X, Wang X, et al (2023) Mitochondria-derived peptide MOTS-c: effects and mechanisms related to stress, metabolism and aging. J Transl Med 21(1): 36.
12. Siddiqui MF, Elwell C and Johnson MH (2016) Mitochondrial Dysfunction in Autism Spectrum Disorders. Autism-Open Access 6(5): 1000190.
13. Khaliulin I, Hamoudi W and Amal H (2025) The multifaceted role of mitochondria in autism spectrum disorder. Mol Psychiatry 30(2): 629-650.
14. Gozal E, Jagadapillai R, Cai J and Barnes GN (2021) Potential crosstalk between sonic hedgehog-WNT signaling and neurovascular molecules: Implications for blood-brain barrier integrity in autism spectrum disorder. J Neurochem 159(1): 15-28.
15. Wells A, Good A, Damyar K, et al (2022) Mass Spectrometry Analysis of Novel Stem Cell-Derived Peptides. Am J Biomed Sci Res 16(2).
16. Lakey, Jonathan RT, Wells A, Good A, et al (2022) Protective Effects of Stem Cell-Derived Peptides in Preventing Autoimmune Diabetes in the Non-Diabetic Mouse Model. Am J Biomed Sci Res 16(5).
17. Onore C, Careaga M and Ashwood P (2012) The role of immune dysfunction in the pathophysiology of autism. Brain Behav Immun 26(3): 383-392.
18. Hu C, Li H, Li J, Luo X and Hao Y (2022) Microglia: Synaptic modulator in autism spectrum disorder. Front Psychiatry 13: 958661.
19. Hughes HK, R J Moreno null and Ashwood P (2023) Innate immune dysfunction and neuroinflammation in autism spectrum disorder (ASD). Brain Behav Immun 108: 245-254.
20. Peng T, Xie Y, Sheng H, Wang C, Lian Y, et al (2022) Mitochondrial-derived vesicles: Gatekeepers of mitochondrial response to oxidative stress. Free Radic Biol Med 188: 185-193.
21. Kumari R and Jat P (2021) Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype. Front Cell Dev Biol 9: 645593.
22. Kroemer G, Galassi C, Zitvogel L and Galluzzi L (2022) Immunogenic cell stress and death. Nat Immunol 23(4): 487-500.
23. Hsiao EY, McBride SW, Chow J, Mazmanian SK and Patterson PH (2012) Modeling an autism risk factor in mice leads to permanent immune dysregulation. Proc Natl Acad Sci USA 109(31): 12776-12781.
24. Bale TL, Davis AM, Auger AP, Dorsa DM and McCarthy MM (2001) CNS region-specific oxytocin receptor expression: importance in regulation of anxiety and sex behavior. J Neurosci Off J Soc Neurosci 21(7): 2546-2552.
25. Caldwell HK, Lee HJ, Macbeth AH and Young WS (2008) Vasopressin: behavioral roles of an “original” neuropeptide. Prog Neurobiol 84(1): 1-24.
26. Ganaiem M, Gildor ND, Shazman S, Karmon G, Ivashko-Pachima Y, et al (2023) NAP (Davunetide): The Neuroprotective ADNP Drug Candidate Penetrates Cell Nuclei Explaining Pleiotropic Mechanisms. Cells 12(18): 2251.
27. Cherepanov SM, Gerasimenko M, Yuhi T, Furuhara K, Tsuji C, et al (20210 Oxytocin ameliorates impaired social behavior in a Chd8 haploinsufficiency mouse model of autism. BMC Neurosci 22(1): 32.
28. Sala M, Braida D, Lentini D, Busnelli M, Bulgheroni E, et al (2011) Pharmacologic rescue of impaired cognitive flexibility, social deficits, increased aggression, and seizure susceptibility in oxytocin receptor null mice: a neurobehavioral model of autism. Biol Psychiatry 69(9): 875-882.
29. Napoli E, Wong S, Hertz-Picciotto I and Giulivi C (2014) Deficits in bioenergetics and impaired immune response in granulocytes from children with autism. Pediatrics 133(5): e1405-1410.
30. Andari E, Duhamel JR, Zalla T, Herbrecht E, Leboyer M, et al (2010) Promoting social behavior with oxytocin in high-functioning autism spectrum disorders. Proc Natl Acad Sci USA 107(9): 4389-4394.
31. Yatawara CJ, Einfeld SL, Hickie IB, Davenport TA and Guastella AJ (2016) The effect of oxytocin nasal spray on social interaction deficits observed in young children with autism: a randomized clinical crossover trial. Mol Psychiatry 21(9): 1225-1231.
32. Wang L, Wang B, Wu C, Wang J and Sun M (2023) Autism Spectrum Disorder: Neurodevelopmental Risk Factors, Biological Mechanism, and Precision Therapy. Int J Mol Sci 24(3): 1819.
33. Rossignol DA and Frye RE (2012) Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis. Mol Psychiatry 17(3): 290-314.
34. Chan MKS, Guo W, Alexander M, Nalapko Y, Jonathan L Peptides Therapy for Neurodegenerative Disorders. Am J Biomed Sci Res 22(6).
35. Guo B, Zhai D, Cabezas E, Welsh K, Nouraini S, et al (2003) Humanin peptide suppresses apoptosis by interfering with Bax activation. Nature 423(6938): 456-461.
36. Lee C, Zeng J, Drew BG, Sallam T, Montalvo AM, et al (2015) The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab 21(3): 443-454.
37. Chan MKS, Wong MB, Casazza K, Jenkins I, Lakey Jonathan RT (2025) Next Gen in Neurorepair: Peptide Therapeutics for the Injured and Aging Brain. Am J Biomed Sci Res 26(6).
38. Chan MKS, Wong MBF, Casazza K, Lakey JRT (2025) Rebuilding the Barrier: Peptide-Based Strategies for Intestinal Regeneration. Am J Biomed Sci Res 26(6).