MicroRNA-425-3p: A Promising Biomarker and Candidate for Pharmacological Intervention in Neuropsychiatric Disabilities with Relevance to Major Depressive Disorder

Abstract

Major depressive disorder (MDD) affects more than 280 million people worldwide and is one of the leading contributors to disability, premature mortality, and overall disease burden. Nearly 60% of individuals who die by suicide have an MDD diagnosis, underscoring its profound impact on both individuals and society. MDD arises from a complex interplay of genetic vulnerability, life experiences, and molecular alterations. Among these, epigenetic mechanisms have received particular attention because they help explain how environmental stress—especially chronic stress—can produce enduring biological changes. MicroRNAs (miRNAs) represent a key class of epigenetic regulators. These small, noncoding RNAs influence the efficiency with which target genes are translated into protein, thereby exerting potent post-transcriptional control over gene expression. Approximately 70% of known miRNAs are expressed in the brain, where they shape neuronal development, synaptic plasticity, and stress responsivity. Dysregulation of miRNA expression can disrupt coordinated gene networks and has been repeatedly associated with impairments in neurogenesis, neurotransmission, neuroinflammation, and endocrine signaling—processes central to the pathophysiology of MDD and other stress-related psychiatric conditions. Within this broader landscape, miR-425 has emerged as a particularly relevant epigenetic regulator across several brain disorders. Alterations in miR-425 expression have been reported in individuals with stress-related conditions and in animal models of chronic stress exposure. Emerging evidence suggests that miR-425 modulates several mood-relevant pathways, including regulation of the hypothalamic–pituitary–adrenal (HPA) axis, neuronal cell death, inflammatory signaling, and antidepressant treatment response as well as key signaling networks such as MAPK and Wnt. Given its regulatory role and disease-associated expression changes, miR-425 has gained significant interest as both a biomarker and a potential therapeutic target. In this review, we examine its biogenesis, molecular targets, and translational importance, positioning miR-425 as a promising candidate for psychiatric intervention strategies. A substantial knowledge gap remains and needs further study. For example, the functions of miR-425 within specific cell types and neural circuits are less defined, and most available evidence derives from rodent studies. Also, the support for miR-425 as a biomarker needs large, standardized, multisite, longitudinal studies integrating neuroimaging, proteomics, and detailed clinical phenotyping. In addition, we are only beginning to understand how pharmacologic and lifestyle interventions influence miR-425 expression. Finally, key downstream targets of miR-425 and safe, cell–type–specific delivery approaches for miR-425–based therapeutics remain underdeveloped. Collectively, these gaps underscore the need for rigorous, multimodal, translational research to determine the potential of miR-425 as both a biomarker and a target for novel treatments.

Plain Language Summary

Major depressive disorder affects hundreds of millions of individuals worldwide and represents a leading cause of disability and suicide. Its development reflects a complex interplay among genetic vulnerability, environmental stressors, and dysregulated gene expression. One key mechanism underlying this dysregulation involves microRNAs (miRNAs), small noncoding RNAs that regulate gene expression in the brain. Many miRNAs are enriched in neural circuits governing mood, stress reactivity, and emotional regulation. Altered microRNA expression can disrupt neuronal communication, inflammatory signaling, and stress-response pathways. Emerging evidence identifies miR-425 as a critical regulator of these processes, highlighting its potential as a biomarker and therapeutic target in depression.

Introduction

Major depressive disorder (MDD) is one of the most prevalent neuropsychiatric illnesses, contributing extensively to global morbidity and mortality rates.¹ Individuals diagnosed with MDD often present with a persistently low mood, marked loss of interest or pleasure in usual activities, and recurrent suicidal ideation. Evidence shows that people with MDD are about 20 times more likely to die by suicide compared to the general population, with around 60% of suicide deaths attributed primarily to this disorder.² The origin of MDD is multifactorial, encompassing genetic predisposition, environmental stressors such as socioeconomic adversity and early life trauma, psychological factors including maladaptive cognition, and biological mechanisms like neuroinflammation and altered neurotransmitter activity.^3–5 Advances in next-generation sequencing and transcriptomics have underscored the critical role of gene expression networks—not just in the regulation of genes but also in their influence on MDD development and suicide risk amplification.⁶

Recent advances have underscored the role of non-coding RNAs (ncRNAs) in the development and progression of MDD. Unlike messenger RNAs, ncRNAs do not encode proteins but instead mediate key gene-regulatory functions. They are broadly classified by length: small non-coding RNAs (sncRNAs) have fewer than 200 nucleotides (nt), whereas long non-coding RNAs (lncRNAs) have more than 200 nt. sncRNAs include miRNAs, small interfering RNAs (siRNAs), and PIWI-interacting RNAs (piRNAs), each contributing to the precise regulation of gene expression. Circular RNAs (circRNAs), which have variable lengths and can overlap with both sncRNAs and lncRNAs, further increase the complexity of RNA-based regulation. Collectively, ncRNAs modulate multiple cellular processes that are critical to the manifestation of psychiatric disorders.^7,8 They regulate messenger RNA (mRNA) expression at transcriptional and post-transcriptional levels, ensuring precise control of protein synthesis. ncRNAs also participate in alternative splicing and epigenetic regulation, including chromatin remodeling and RNA editing, and can act on genes located nearby (cis) or at a distance (trans) from their own transcription sites.⁹ Overall, ncRNAs serve as crucial intermediaries, translating genetic information into cellular phenotypes and playing important roles in the pathophysiology of complex disorders such as MDD.

Of all non-coding RNAs, miRNAs are the most extensively characterized across both human and animal systems.^10,11 These molecules are classified as sncRNAs, typically 19–25 nucleotides long. MiRNAs can move between subcellular compartments and even cross the blood–brain barrier, where they engage in key regulatory processes.¹² These activities are involved in development, cell differentiation, and the maintenance of cellular homeostasis. A single miRNA can regulate hundreds of mRNA targets, while individual mRNAs can be controlled by multiple miRNAs, creating a highly complex, interconnected gene regulatory network.^8,12,13

Research on miRNAs has rapidly expanded, revealing their major role in brain physiology. Roughly 70% of known miRNAs are expressed in the brain, where they regulate post-transcriptional mechanisms essential for neuronal growth, differentiation, plasticity, and synapse formation.¹⁴ Dysregulated miRNAs have been linked to diverse conditions, including neuropsychiatric and neurodegenerative diseases, cancer, cardiovascular disease, autoimmune disorders, and metabolic syndromes.^12,15–19 Specifically, regarding the nervous system, miRNAs help to control neurogenesis, synaptic function, inflammation, protein folding, and neuron survival.^14,20,21 Altered miRNA expression is now recognized as a contributing factor in multiple neuropsychiatric and neurodegenerative disorders, including MDD, bipolar disorder, anxiety, autism, schizophrenia, Alzheimer’s disease, and Parkinson’s disease.^22–24

Among these regulatory miRNAs, miR-425 has recently emerged as a molecule of particular interest due to its significant regulatory roles in the brain and neurological diseases. This review focuses on miR-425-3p and its regulatory role in neuropsychiatric disorders, with particular emphasis on its potential as a biomarker and therapeutic target in MDD. Current antidepressant treatments are limited by variable treatment efficacy, incomplete remission rate, and limited potential. This underscores the need for a biomarker-driven, epigenetics-based therapeutic candidate that can potentially overcome these limitations in treating MDD patients. In this connection, being a stress-responsive miRNA, the role of miR-425-3p remains insufficiently characterized in stress-associated psychiatric conditions like MDD. This underscores a critical gap in understanding its mechanistic and clinical relevance. To date, only one study from our laboratory has examined this miRNA, identifying miR-425-3p as stress-responsive miRNA in a rat preclinical model of chronic stress. MiR-425-3p is notably expressed in neurons and has been implicated in modulating various molecular pathways critical to brain function, including neurogenesis and synaptic activity. Recent studies demonstrate the role of miR-425-3p in neurodegenerative disorders.^10,24 Beyond neurodegeneration, miR-425 has been shown to regulate key genes in the MAPK and Wnt signaling pathways, both of which are implicated in mood regulation and MDD.²⁵ Activation of these pathways has been strongly associated with a decrease in depressive symptoms and improved antidepressant response.²⁵ Its dysregulation is associated with altered neuronal plasticity and stress response, highlighting miR-425 as a potential biomarker and therapeutic target for neuropsychiatric disorders, including MDD.^26,27 Current research is also exploring the involvement of miR-425-3p in vascular dementia and microglial activation, further reinforcing its multifaceted roles in brain health and disease. Predictive analyses and in vivo models continue to refine our understanding of miR-425-3p, its specific targets, and its mechanistic contributions to neurobiology and neuropathology. Considerable attention has turned to the translational potential of miR‑425-3p and other miRNAs as biomarkers and therapeutic targets in various brain disorders.^28,29 Although early evidence suggests that miR-425-3p may play a role in neuropsychiatric disorders, the current research is still limited. There is a lot of variation in study design, sample types, and clinical settings. Because of this, future work should focus on careful validation and more standardized methods to better clarify its role. Despite some limitations, miR-425-3p is a strong candidate because it is involved in key neurological pathways. It is also important both as a biomarker and as a potential therapeutic target, which supports its prioritization in the present review.

Biogenesis of miRNA – Canonical Pathway

In the canonical pathway, seen in Figure 1A, miRNA production begins inside the nucleus. Primary miRNA transcripts (pri-miRNAs) are generated through RNA polymerase II activity. These transcripts are then cleaved by the nuclear RNase III enzyme Drosha, generating precursor miRNAs (pre-miRNAs). The pre-miRNAs are exported into the cytoplasm by the Exportin-5 and Ran-GTP transport system. Once in the cytoplasm, another RNase III enzyme, Dicer, trims pre-miRNAs into mature miRNAs. These mature miRNAs are loaded into the RNA-induced silencing complex (RISC), where they regulate gene expression by binding mainly to the 3′ untranslated regions of messenger RNAs. This binding suppresses gene expression through three possible mechanisms: (1) blocking translation by interfering with the ribosome or elongation factors, (2) promoting mRNA degradation through decapping and exonuclease activity, or (3) promoting degradation via deadenylation.⁷ Like other microRNAs, hsa-miR-425-3p is transcribed primarily by RNA polymerase II as a long primary transcript (pri-miR-425). Shown in Figure 1B, the pri-miRNA is processed in the nucleus by the microprocessor complex, consisting of DROSHA and DGCR8, into a precursor hairpin structure (pre-miR-425). The pre-miRNA is then exported to the cytoplasm through Exportin-5, where the RNase III enzyme Dicer cleaves the terminal loop to generate a mature miRNA duplex. This duplex is loaded onto an Argonaute (Ago1–4) protein within the RISC, where the passenger strand is degraded, leaving a functional single-stranded mature miR-425. Genomically, hsa-miR-425 is located within the first intron of the DALRD3 (DALR anticodon binding domain containing 3) gene on chromosome 3p21.31. As an intronic miRNA, it is co-transcribed with its host gene and subsequently processed by the canonical miRNA biogenesis pathway described above, ultimately yielding the mature functional strand, hsa-miR-425-5p.³⁰

Figure 1.

Canonical miRNA biogenesis and generation of hsa-miR-425-3p. (A) miRNA genes are transcribed by RNA polymerase II to produce primary miRNA transcripts (pri-miRNAs). These transcripts are processed in the nucleus by the microprocessor complex, composed of DROSHA and DGCR8, to generate precursor miRNAs (pre-miRNAs). Pre-miRNAs are exported to the cytoplasm by Exportin-5, where Dicer cleaves the terminal loop to form a mature miRNA duplex. The duplex is then loaded onto an Argonaute (Ago1–4) complex, and removal of the passenger strand yields the functional single-stranded mature miRNA (shown in blue). (B) In humans, hsa-miR-425 is encoded within an intron of the DALRD3 gene and is co-transcribed with its host gene as part of the miR-191/425 intronic cluster. Transcription by RNA polymerase II generates a primary transcript containing the miR-425 hairpin (pri-miR-425), which is subsequently processed in the nucleus by the microprocessor complex composed of DROSHA and DGCR8 to produce pre-miR-425. The pre-miR-425 is exported to the cytoplasm via Exportin-5 and further cleaved by Dicer to generate a mature miRNA duplex. Following Argonaute loading and strand selection, mature single-stranded hsa-miR-425 is produced.

Abbreviations: DGCR8, DiGeorge Syndrome Critical Region 8; Ago, Argonaute; DALRD3, DALR anticodon binding domain-containing protein 3.

Key Neuronal Functions of miR-425

The study of epigenetics encompasses the interaction between the environment and genetics. Epigenetic mechanisms, such as DNA methylation, histone modification, and the activity of noncoding RNAs, are essential for regulating gene expression in response to environmental stimuli. The current literature has revealed miRNAs as crucial modulators of neuronal gene expression and synaptic plasticity.^31,32 These small noncoding RNAs fine-tune the transcriptional landscape by repressing translation or promoting the degradation of target messenger RNAs, thereby influencing processes such as neurodevelopment, synaptic remodeling, and stress adaptation. Increasing evidence links dysregulated miRNA expression to neuropsychiatric disorders, including depression and schizophrenia.^33,34 Additionally, extensive research on miRNAs’ role in neurodegenerative diseases like Alzheimer’s disease suggests that miRNAs may act as molecular switches in maintaining neuronal homeostasis.³² By functioning as regulatory nodes within gene networks, miRNAs provide a dynamic layer of control that integrates genetic and environmental influences on brain function.^22,35

In mouse central nervous system tissues, miR-425-3p expression has consistently been shown to be enriched in microglia and other immune cells and is highly conserved across vertebrate species.^6,31 In humans, the DALRD3 locus has been associated with various brain-related traits.³⁰ It has been documented that miR-425-3p plays an important role in regulating neuronal survival and brain homeostasis. Additionally, it has been linked to neurodevelopment, synaptic regulation, and neuroprotection.²⁹ As mentioned earlier, miR-425-3p is processed from a precursor hairpin structure located within the miR-191/425 cluster, giving rise to two mature isoforms, miR-425-5p and miR-425-3p. Both isoforms participate in the post-transcriptional regulation of target mRNAs by binding to complementary sequences in their untranslated regions, thereby repressing translation or promoting degradation. In the central nervous system, altered levels of miR-425-3p have been observed in several neurodegenerative and psychiatric conditions, including Alzheimer’s disease, Parkinson’s disease, and major depressive disorder, suggesting that it contributes to disease pathophysiology through modulation of signaling pathways such as PI3K/Akt, GSK-3β, and MAPK.^{5,10,16,22,29,36} Experimental models indicate that miR-425-3p loss can impair neuronal function and promote cell death, whereas restoring its levels protects against neurodegeneration. Collectively, these findings highlight miR-425-3p as a key regulator of neural integrity and a potential biomarker for neurological disorders.^16,20,23,37

Emerging Role of miR-425 in Neuropsychiatric Disorders

MiR-425-3p is emerging as a multifunctional regulator in the central nervous system, with overlapping roles in both neuropsychiatric and neurodegenerative conditions. Evidence indicates that it modulates key signaling pathways, including PI3K/Akt, MAPK, Wnt, and apoptosis-associated pathways, thereby influencing neuronal survival, synaptic plasticity, and stress-response mechanisms.^25,28 Additionally, miR-425-3p is involved in cortical neuron migration, neuroinflammation, Wnt signaling, and neuronal repair. A schematic diagram depicting these functions is provided in Figure 2. In major depressive disorder, altered miR-425-3p expression is associated with disrupted stress signaling and antidepressant response. Bioinformatic analyses suggest that miR-425-3p functions as a hub regulator, coordinating multiple gene networks rather than acting on isolated targets, which may explain its involvement across diverse neurological contexts.²⁵ Collectively, these findings highlight the converging roles of miR-425-3p as both a biomarker and a potential modulator of disease-relevant pathways, though further studies are required to clarify causality and therapeutic potential.

Figure 2.

MiR-425-3p regulates multiple aspects of neuronal function and homeostasis. Shown clockwise are eight miR-425-3p–associated processes: cortical neuron migration, neuroinflammation, synaptic plasticity, Wnt signaling, neuronal survival, neuronal repair, apoptosis, and MAPK activity, illustrating the broad and coordinated influence of miR-425-3p on neuronal dynamics.

Abbreviations: Wnt, Wingless-related integration site; MAPK, Mitogen-Activated Protein Kinase.

Using small RNA sequencing of paired peripheral blood samples collected before and after antidepressant treatment, a study identified miR-425-3p as significantly associated with clinical response in patients with major depressive disorder.^10,21,38 Differential expression of miR-425-3p was observed specifically in treatment responders and was replicated across independent patient cohorts and a complementary mouse model. Integrated transcriptomic and pathway analyses further demonstrated that miR-425-3p is linked to molecular networks involved in MAPK and Wnt signaling, implicating this miRNA in biological processes underlying neuronal plasticity and antidepressant response. Integrative target prediction and pathway enrichment analyses further indicated that putative miR-425-3p targets are significantly enriched in MAPK and Wnt signaling pathways. Among these, neuroplasticity-related genes such as NTRK2 and FGF2 were identified as candidate targets and showed expression patterns associated with miR-425-3p levels in clinical samples. Consistent with these predictions, in vitro overexpression of miR-425-3p reduced the expression of multiple pathway components, supporting a regulatory role for miR-425-3p in signaling networks relevant to MDD and treatment response.^25,39

Role of miR-425-3p in Neurodegenerative and Neurodevelopmental Disorders

miR-425-3p in Parkinson’s Disease

In Parkinson’s disease (PD), miR‑425 functions as an important modulator of neuronal survival pathways, with both experimental and clinical data supporting its involvement in disease progression. Preclinical studies indicate that loss or deficiency of miR-425-3p promotes necroptosis, a regulated and inflammatory form of cell death. Although necroptosis resembles necrosis under the microscope, it is tightly controlled by specific signaling proteins rather than resulting from accidental injury. This process accelerates dopaminergic neuron degeneration in the substantia nigra and contributes to the worsening of motor symptoms.²⁸ miR-425-3p deficiency was directly linked to activation of the necroptotic program 9 (shown in summary in Figure 3) in dopaminergic neurons, a regulated form of cell death initiated by receptor-interacting protein kinase 1 (RIPK1).⁴⁰ In an MPTP mouse model of Parkinson’s disease, reduced miR-425-3p levels in the substantia nigra were correlated with upregulation of necroptotic mediators, including RIPK1, RIPK3, and phosphorylated MLKL, and this coincided with dopaminergic neuron loss and motor dysfunction, indicating functional necroptosis activation. Mechanistically, miR-425-3p was shown to target the 3′ untranslated region of RIPK1 mRNA, such that inhibition of miR-425-3p increased RIPK1 expression and enhanced necroptotic signaling — effects that were confirmed by luciferase reporter assays and reversed by the necroptosis inhibitor Nec-1.²⁸ In cultured neuronal cells, miR-425-3p inhibition promoted expression of RIPK1 and MLKL/pMLKL and increased cell death, while in human Parkinson’s disease brain tissue, miR-425-3p levels were found to be markedly reduced with concomitant increases in RIPK1, RIPK3, and pMLKL.²⁸ Moreover, genetic knockdown of miR-425-3p in mice exacerbated MPTP-induced neurodegeneration, whereas intracerebral delivery of miR-425-3p mimics attenuated necroptotic activation, preserved dopaminergic neurons, and improved behavioral deficits, strongly supporting a causal role for miR-425-3p in restraining necroptosis and neuronal loss.²⁸

Figure 3.

Reduced miR-425-3p expression and neurodegenerative signaling. Decreased expression of miR-425 leads to attenuation of the Wnt/β-catenin signaling pathway, accompanied by reduced expression of genes involved in cell adhesion and neural connectivity. In parallel, loss of miR-425-3p is associated with activation of the RIPK1-dependent signaling pathway and its downstream gene network, promoting pro-degenerative signaling and increased neuronal cell death.

Abbreviation: RIPK1, Receptor-Interacting Serine/Threonine-Protein Kinase 1.

Additionally, it was shown that restoring miR‑425-3p expression can attenuate necroptotic signaling and protect dopaminergic neurons, emphasizing its protective role in maintaining neuronal integrity within vulnerable midbrain regions.²⁸ Clinically, circulating miR‑425-3p levels are reduced in the peripheral blood of PD patients, and this decrease is even more pronounced in those with comorbid depression (PD-D), suggesting that alterations in miR‑425-3p may reflect both neurodegenerative and neuropsychiatric components of the disease.³⁸ Additionally, lower miR‑425-3p concentrations correlate with depressive symptomatology in PD, supporting its potential utility as a minimally invasive biomarker for identifying PD patients at risk of mood disturbances. Taken together, these findings highlight miR‑425-3p as a promising therapeutic target, with strategies aimed at enhancing its expression or mimicking its function potentially helping limit necroptosis-driven neuronal loss and improving both motor and non‑motor outcomes in PD.^28,38

miR-425-5p in Alzheimer’s Disease

In Alzheimer’s disease (AD), miR-425-5p has emerged as an important regulator of neuronal survival and tau pathology by directly modulating stress‑response pathways in neurons.^29,41 Experimental studies in AD models have shown that increased expression of miR-425-5p not only enhances tau phosphorylation but also markedly promotes neuronal apoptosis, linking this microRNA to both cytoskeletal disruption and cell death. Mechanistically, miR-425-5p exerts these effects by targeting heat shock protein B8 (HSPB8), a molecular chaperone that normally facilitates the clearance of misfolded or aggregated proteins and contributes to proteostasis in the nervous system.²⁹ Suppression of HSPB8 by miR-425-5p weakens this protective protein quality-control machinery, which in turn favors activation of kinases such as glycogen synthase kinase-3β (GSK-3β), leading to increased tau phosphorylation and accumulation of pathological tau species. This combination of impaired protein clearance and elevated tau phosphorylation ultimately sensitizes neurons to apoptotic pathways, reinforcing the concept that upregulated miR-425-5p is a pathogenic driver in AD and a potential therapeutic target for modulating tau-related neurodegeneration.²⁹ In addition, miR-425 has been observed to negatively regulate amyloid precursor protein processing, and its downregulation in AD correlates with increased amyloid-beta aggregation and neurodegeneration.¹⁰ MiR-425 also influences neuroinflammatory and immune-related processes, which are crucial in neurodegenerative conditions.^3,41,42

Biomarker and Therapeutic Potential of miR-425 in Neuropsychiatric Disorders

MiR-425 has emerged as a promising biomarker and molecular effector in neuropsychiatric disorders, with converging evidence from clinical cohort studies and preclinical models supporting both its diagnostic and therapeutic relevance in MDD and PD.^25,38,43 The two subtypes of circulating miR-425 (miR-425-3p and miR-425-5p) show disorder- and context-specific alterations, and their levels correlate with treatment response, structural brain changes, and neurodegenerative mechanisms, positioning miR-425 as a candidate marker for disease stratification and longitudinal monitoring.^25,29,44,45

Biomarker Role in MDD

In MDD, alterations in circulating miR-425-3p have been characterized in well-defined clinical cohorts using standardized blood collection and quantitative PCR–based profiling. In the study by von Auwera et al,⁴⁴ patients with MDD and healthy controls were recruited from observational cohorts, and plasma or serum miRNAs were isolated using column-based extraction, followed by reverse transcription and quantitative real-time PCR (qRT-PCR) or small RNA sequencing to quantify miR-425-3p expression. The investigators applied linear models and regression analyses to examine associations between baseline miR-425-3p levels, depression diagnosis, and symptom severity, and then assessed changes in expression in relation to antidepressant treatment response over follow-up. Reduced miR-425-3p expression was particularly evident in individuals who responded clinically to antidepressant therapy, suggesting that miR-425-3p dynamics may reflect treatment-induced molecular adaptations rather than nonspecific illness burden.^34,44 Beyond simple case–control contrasts, the study incorporated covariate adjustments for age, sex, and medication, and performed sensitivity analyses across different antidepressant classes, which strengthened the interpretation of miR-425-3p as a state- and treatment-sensitive marker. These methodologically rigorous approaches indicate that serial measurement of circulating miR-425-3p could be used to monitor therapeutic efficacy and potentially guide personalized interventions in MDD.^34,44,46

Computational analyses play a critical role in uncovering the potential regulatory functions of microRNAs in neuropsychiatric disorders, especially when direct functional studies are limited. In the case of miR-425-3p, integrative in silico approaches in the study by López et al utilized multiple miRNA target prediction databases combined with transcriptomic correlations to identify putative mRNA targets and enriched signaling pathways, revealing significant associations with MAPK and Wnt networks implicated in neuronal plasticity and antidepressant response in major depressive disorder.¹ These computational predictions provided a framework for nominating genes for further expression correlation and functional evaluation, underscoring the value of bioinformatic prioritization in miRNA research. Additional clinical evidence further supports the relevance of miR-425-3p to mood dysregulation: circulating miR-425-3p levels are significantly downregulated in depressed patients with Parkinson’s disease and negatively correlate with depression severity, suggesting that miR-425-3p may serve as a biomarker of depressive phenotypes across neurological conditions.³⁸ Population studies also link circulating miR-425-5p to brain white matter lesions and immunological processes, indicating broader involvement in brain structural and inflammatory mechanisms that may intersect with depression pathophysiology.^25,45 Although mechanistic data specific to depression remain sparse, these computational and biomarker studies collectively highlight miR-425’s potential to influence signaling networks and neurobiological processes relevant to MDD, illustrating the importance of continuing in silico and experimental investigations to clarify its role in maladaptive neuropsychiatric alterations.^9,25,38

Structural Brain Changes and miR-425

MiR-425-5p has also been linked to macrostructural and microstructural brain alterations, supporting its role as a peripheral mirror of central neurobiological processes. In work by López et al,²⁵ subjects underwent detailed neuroimaging—typically structural MRI with lesion mapping and quantitative assessment of white matter hyperintensities or microvascular lesions—combined with blood sampling for peripheral miRNA profiling. Circulating miR-425-5p levels were measured using standardized RNA extraction from plasma or serum and qRT-PCR with specific stem-loop primers, with normalization to stable endogenous controls to minimize technical variability.

Statistical analyses related miR-425-5p expression to total white matter lesion burden and regional lesion distribution, often using voxel-based analyses or lesion volume quantification, and controlled for vascular risk factors and demographic variables. Lower or dysregulated miR-425-5p expression correlated with greater white matter lesion load, indicating that miR-425-5p may index neuroinflammatory and neurodegenerative changes that underlie white matter damage. These findings imply that miR-425-5p could serve as a non-invasive indicator of structural brain integrity and disease progression in disorders with prominent white matter pathology.^44,46

Circulating miR-425 in PD and Mood Symptoms

In PD, clinical studies have assessed miR-425-3p expression in peripheral blood samples from PD patients with and without depression, as well as from neurologically healthy controls. Liu et al,³⁸ collected venous blood, isolated serum or plasma, and extracted total RNA enriched for small RNAs, followed by qRT-PCR quantification of miR-425-3p using specific primers and internal reference miRNAs for normalization. The study applied group comparisons and receiver operating characteristic (ROC) curve analyses to evaluate the diagnostic utility of miR-425-3p levels, and correlation analyses to link miR-425-3p expression with clinical scales of depressive symptoms in PD (such as HAMD or similar instruments). Circulating miR-425 was significantly downregulated in PD patients, with further reductions in those with comorbid depression (PD-D), and miR-425-3p levels showed negative correlations with depression severity scores, supporting its potential as a dual biomarker of neurodegeneration and mood disturbance. These method-based findings suggest that miR-425-3p measurement in blood could aid in identifying PD patients at risk for depression and monitoring non-motor symptom trajectories.³⁸

Therapeutic Potential of miR-425-3p

Beyond its biomarker role, miR-425-3p has been investigated as a functional regulator in experimental models, particularly in PD-related neurodegeneration. Hu and colleagues^10,28 used in vitro and in vivo approaches to manipulate miR-425-3p expression and characterize downstream effects on cell death pathways and dopaminergic neuron survival. In cellular models, dopaminergic or neuronal cell lines were exposed to PD-relevant toxins (eg., 6-hydroxydopamine or MPP⁺), and miR-425-3p levels were modified using synthetic miR-425-3p mimics, inhibitors, or lentiviral vectors delivering miR-425-3p overexpression or knockdown constructs. Cell viability assays, flow cytometry, and Western blotting for necroptosis markers (such as RIPK1, RIPK3, and MLKL) and apoptosis markers were used to determine how miR-425-3p affects regulated cell death signaling.^10,28 Across both models, miR-425-3p acts as a conserved neuronal suppressor of degenerative cascades. In AD, it restrains APP/BACE1-driven amyloid genesis and PTEN-mediated PI3K-Akt suppression; in PD, it restrains RIPK1-mediated necroptosis. In both diseases, in vivo delivery of miR-435 mimics (AgomiR-425) into the brain reverses key molecular and cellular pathologies and improves behavioral outcomes in mouse models, supporting miR-425-3p replacement as an experimentally validated disease-modifying strategy with translational potential.^10,28

In animal models, rodents received stereotaxic injections of viral vectors encoding other related miRNAs or control constructs into the substantia nigra or striatum, followed by neurotoxin administration to induce dopaminergic degeneration.^47,48 Behavioral tests (including rotarod, open field, and pole test) evaluated motor function, while immunohistochemistry for tyrosine hydroxylase and necroptosis markers assessed dopaminergic neuron integrity and cell death in the nigrostriatal pathway. miR-425-3p deficiency promoted necroptosis and exacerbated dopaminergic neuron loss, whereas restoration or overexpression of miR-425-3p attenuated necroptotic signaling, preserved neuron numbers, and improved motor performance, highlighting its protective role.^6,28,49

Pathways Regulated by miR-425 and Intervention Strategies

Mechanistic studies indicate that miR-425-3p targets genes in key signaling pathways involved in neuronal survival, stress response, and synaptic plasticity, including components of the PI3K/Akt, MAPK, and Wnt cascades. Using bioinformatic target prediction, luciferase reporter assays, and Western blotting, it has been shown that altering miR-425-3p expression changes the levels and activity of pathway members, thereby modulating downstream pro-survival or pro-death signaling.²⁸

In preclinical models, overexpression of miR-425-3p activated pro-survival pathways such as PI3K/Akt, reduced inflammatory mediator expression, and decreased neuronal apoptosis markers, while miR-425 inhibition had the opposite effects. These pathway-level changes translated into improved behavioral outcomes in animal models, including better motor performance in PD paradigms and reduced indices of neuroinflammation and neurodegeneration.²⁸

The methodological foundation of these studies supports the feasibility of miR-425-3p–based interventions, such as chemically stabilized miR-425-3p mimics to enhance its activity or antisense inhibitors to suppress pathological overexpression in specific contexts. Delivery modalities explored include viral vectors, lipid-based nanoparticles, and intranasal or intracerebral administration, each assessed for efficiency, regional specificity, and safety in rodent models. Collectively, this work suggests that rational modulation of miR-425-3p could potentially restore more physiological signaling in PI3K/Akt, MAPK, and Wnt pathways, limit neuronal loss, and ultimately alleviate both motor and affective symptoms across neuropsychiatric disorders.^32,50,51 Despite these promising findings, the current evidence remains limited, especially in neuropsychiatric conditions. Only a few studies have looked at it directly in patients. As a result, we do not yet have strong confirmation of the findings in separate groups of people, and there are very few direct comparison studies. Moreover, the available studies often use different experimental methods or address slightly different biological questions, making the results harder to compare and interpret. Taken together, these limitations highlight the need for focused, large-scale, and well-designed studies to confirm current findings and further elucidate the role of miR-425-3p in these conditions.

Summary and Future Directions

In this review, we examined the emerging significance of miR-425-3p and its multifaceted roles across neuropsychiatric and neurodegenerative disorders. As highlighted, miR-425-3p is a brain-enriched miRNA that exerts broad regulatory influence over several molecular signaling pathways essential for neuronal survival, synaptic plasticity, cellular stress responses, and overall neurobiological homeostasis. Accumulating evidence suggests that miR-425-3p interfaces with a wide array of intracellular networks, including PI3K/Akt, MAPK, Wnt, and necroptosis-related signaling cascades, placing it at a central node of multiple processes that govern cell fate and neural integrity. Our predictive and experimental analyses indicate that miR-425-3p modulates key target genes associated with apoptosis, tau phosphorylation, dopaminergic neuron maintenance, and neuroimmune activity. These diverse regulatory functions collectively support the concept that miR-425-3p plays a foundational role in sustaining neuronal health and regulating pathways that are disrupted in various neuropsychiatric and neurodegenerative conditions.

Particular attention is warranted for the altered expression patterns of miR-425-3p observed in MDD, Parkinson’s disease, and Alzheimer’s disease. In each of these conditions, dysregulation of miR-425-3p appears to contribute to disease pathophysiology through both direct targeting of critical neuronal genes and indirect modulation of broader regulatory networks. Beyond its mechanistic relevance, miR-425-3p has emerged as a promising biomarker for disease progression, treatment responsiveness, and structural brain changes—including white matter integrity—highlighting its potential utility in clinical stratification and therapeutic monitoring.

Taken together, these findings show that miR-425-3p has strong clinical potential. It may serve as a minimally invasive biomarker and also as a modifiable therapeutic target in neuropsychiatric disorders. Because miR-425-3p can be detected in peripheral biofluids, it could be useful for early diagnosis, patient stratification, and tracking how patients respond to treatment. In addition, growing evidence about its functional role suggests that it may be suitable for targeted therapies. However, several challenges remain before it can be used in the clinic. These include the need to test it in large, well-characterized patient groups and to standardize its measurement. We also need a better understanding of its tissue-specific effects and the most effective for its delivery. Addressing these issues will be critical to bring miR-425-3p from experimental research into clinical use.

While current findings emphasize the importance of miR-425-3p in neuropsychiatric and neurodegenerative disorders, several key areas still need further investigation. For example, although miR-425-3p expression has been observed in neurons and microglia, its cell-type–specific effects are not well understood.⁵² Tools like single-cell sequencing, spatial transcriptomics, and cell-targeted manipulation are necessary to determine which neural populations are most affected by miR-425-3p perturbation. Additionally, most mechanistic research relies on rodent models. Human postmortem studies are essential to confirm pathway-level effects and to map miR-425’s role across different brain regions. While miR-425-3p shows promise as a biomarker, more extensive, multi-site studies are required—standardized miRNA isolation and quantification, longitudinal data across disease stages, and integration with imaging, proteomics, and clinical outcomes. Such data could facilitate patient stratification and personalized treatment strategies. Since miR-425-3p has been linked to MDD, PD, AD, and vascular dementia, comparing its functions across these conditions may uncover common mechanisms involving neuroinflammation, loss of plasticity, and neurodegeneration. Lastly, little is known about how antidepressants, anti-inflammatory agents, neuroprotective drugs, or lifestyle interventions (such as stress reduction and exercise) influence miR-425-3p. Given the small size, conserved sequence, and relative stability of miRNAs, miR-425-3p is a promising candidate for therapeutic development. Developing cell-type-specific delivery systems, such as lipid nanoparticles or extracellular vesicles, could allow targeted restoration or inhibition of miR-425-3p to modulate disease-relevant pathways.⁴¹ Nevertheless, further research is needed to fully elucidate the molecular mechanisms, refine delivery strategies, and safely translate miR-425-3p-based therapies into clinical practice.^{9,15,26,35,53}

Funding Statement

This work was supported by funding from the National Institute of Mental Health (R01MH130539, R01MH124248, R01MH118884, R01MH128994, R01MH107183, and R56MH138596) and American Foundation for Suicide Prevention (DIG-0-047-24) to Dr. Dwivedi.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare no competing interests in this work.