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Page 407 Aydin et al. J Transl Genet Genom. 2025;9:406-26 https://dx.doi.org/10.20517/jtgg.2025.108

and healthy controls. Therefore, these hub genes might be proposed as potential DMD-specific network
biomarkers. Also, a drug repositioning analysis was conducted, revealing that celastrol, emetine dihydrochloride
hydrate, radicicol, withaferin-A, and apigenin triacetate were reported as potential drugs for the management of
DMD pathogenesis. The docking analysis with these repositioned drug candidates showed significant binding
affinities among 17 network biomarkers (SQSTM1, PML, SPTAN1, SPTBN1, KIAA1429, SOX4, SP1, SPP1, NFKB1, TP53,
NKX3-1, CIITA, ARL6IP1, IGFBP5, OCIAD2, RAP2B, and NFIB).

Conclusion: Celastrol and emetine dihydrochloride hydrate were the two repurposed small molecules that
demonstrated effective docking results compared with inhibitors of hub genes and with the clinically used DMD-
specific drug vamolorone. Further studies should be conducted to recapitulate these findings through in vitro and in
vivo studies.

Keywords: Transcriptomics, Duchenne muscular dystrophy, drug repositioning, celastrol, emetine

INTRODUCTION
Duchenne Muscular Dystrophy (DMD), with an incidence of 1 in 3,000-5,000 male births, is an X-linked
(Xp21.1) recessive neuromuscular disease characterized by dystrophin gene mutations that result in loss of
function of the dystrophin protein . The majority of mutations (about 60%) are deletions, while the
[1]
[2]
remaining 40% include duplications and frameshift mutations . These mutations occur in hotspot regions
of the DMD gene, specifically exons 3-9 and 45-55 .
[3-5]

The dystrophin protein provides an essential connection between the sarcolemmal cytoskeleton of muscle
cells and the extracellular matrix, thereby preserving muscle function . In the absence of dystrophin
[6]
protein, the sarcolemma is damaged and membrane stabilization is disrupted, facilitating the entry of small
molecules and calcium ions into the cell . This causes increasing complications and pathological changes
[6,7]
in muscle cell dysfunction and muscle cell fiber degeneration, eventually resulting in death . DMD
[6,8]
pathogenesis might cause some comorbidities such as gait disorders, difficulty in climbing stairs, scoliosis,
cardiomyopathy, respiratory system disorders, and neurologic/neuropsychiatric problems . Depending on
[9]
the complications accompanying these disorders, the life expectancy of patients is approximately 20-30
years . DMD has been generally diagnosed by biopsies, blood tests, and physical assessment to measure
[8]
motor dysfunction.

Novel therapeutic developments rely on biomarkers that hold great promise for precise management
strategies and provide potential disease indicators. Biomarkers used in blood tests for DMD diagnosis
include inflammatory markers [e.g., cytokines such as interleukin-6 (IL-6)], microRNAs [miRNAs, such as
muscle-specific miRNAs (myomiRs)], and metabolites (e.g., creatine kinase levels), which reflect
myonecrosis in DMD [10,11] . Recent developments in DMD treatments include gene therapies, exon-skipping
vaccines, drugs, genome-editing techniques, anti-inflammatory drugs, and corticosteroids to reduce
symptoms [2,12,13] . Although these treatments reduce the course of the disease, they do not provide a complete
[14]
cure because they cover only a certain percentage of mutations .

The majority of DMD-specific research published in the literature has used single-step omics data.
Although recent DMD treatments generally focus on gene therapies, a comprehensive multi-omic approach
may better uncover the molecular mechanisms of the disease by addressing the limitations of gene therapy-
based strategies. Such an approach could provide a more advanced understanding of disease pathogenesis
and therapeutic modalities. In this study, molecular networks integrating multi-omic data were constructed
based on high-throughput transcriptome data to elucidate disease-specific biomarkers. Furthermore, the