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Page 419 Aydin et al. J Transl Genet Genom. 2025;9:406-26 https://dx.doi.org/10.20517/jtgg.2025.108

[111]
dopamine levels, prevent dopaminergic neuron death, and alleviate locomotor dysfunction . A
bioinformatics study found a link between NR1D2 gene expression and mitochondrial quality control, with
mitochondrial dysfunction contributing to DMD. Docking analysis between the NR1D2 gene and celastrol
[112]
suggested that celastrol could be used to treat colorectal muscular atrophy . Celastrol has also been
repurposed for the treatment of breast cancer, COVID-19, and human papillomavirus (HPV)18-based
cervical cancer [113-115] . Celastrol has not previously been reported as a repositioned drug for the treatment of
DMD.

Emetine, or emetine dihydrochloride hydrate, is an isoquinoline alkaloid and an antiprotozoal drug
obtained from the alizarin family of the Carapichea ipecacuanha species [116,117] . Emetine, an FDA-approved
[77]
small molecule, has been used to treat amoebic liver abscesses, malaria, and intestinal infections . It is
effective in inhibiting protein synthesis in mammalian cells. Emetine has been reported to disrupt
messenger RNA (mRNA)-eIF4E interactions and is therefore proposed as an effective compound for
[118]
inhibiting viral polymerases . It induces apoptosis by regulating apoptotic factors . Drug repositioning
[116]
of emetine dihydrochloride hydrate has previously been explored for antimalarial drug trials, Alzheimer’s
disease, SARS-CoV-2, breast cancer, and squamous cell carcinoma [77,119] . Emetine dihydrochloride hydrate/
emetine has not previously been reported as a repositioned drug for the treatment of DMD.

All these drugs may have the potential to exert therapeutic effects on DMD. Among these five drugs,
celastrol and emetine exhibited the highest binding affinities, with percentages of 91% (n = 30 out of 33
DMD biomarkers) and 76% (n = 25 out of 33 DMD biomarkers), respectively. These drugs bind effectively
to genes including SQSTM1, PML, SPTAN1, SPTBN1, KIAA1429, SOX4, SP1, SPP1, NFKB1, TP53, NKX3-1,
CIITA, ARL6IP1, IGFBP5, OCIAD2, RAP2B, and NFIB, which are involved in inflammation, infection,
autophagy, and apoptosis-related biological processes. Therefore, celastrol is proposed as an efficient
candidate, either alone or in combination with emetine. Together, they may exert a synergistic effect in
managing DMD by enhancing anti-inflammatory responses, reducing oxidative stress, inducing apoptosis,
and promoting the scavenging activities of the drugs. The possible mechanisms of action of celastrol are
detailed in the following sections.

Celastrol was reported to increase SIRT3 gene expression, which is associated with oxidative stress and has
an inflammation-lowering effect . Another study reported that the absence of dystrophin in DMD
[120]
pathogenesis leads to oxidative stress . In this regard, celastrol might be considered to have an oxidative
[121]
stress-reducing effect in DMD. It has been observed that pro-inflammatory cytokine levels controlled by
NF-κB, examined in dystrophic muscles of DMD patients, are expressed at much higher levels than
normal . Inhibiting NF-κB promotes muscle regeneration in DMD . Additionally, in biopsies from
[123]
[122]
Crohn’s disease patients, celastrol suppressed the production of pro-inflammatory cytokines, especially
tumor necrosis factor-α (TNF-α) . Celastrol functions as an immunomodulatory agent to minimize
[124]
excessive inflammation by modulating TNF-α and IL-6 . Celastrol’s well-characterized ability to modulate
[125]
NF-κB signaling, suppress pro-inflammatory cytokines, and attenuate oxidative stress [105,126] is directly linked
to the chronic inflammation and ROS accumulation that drive muscle degeneration in DMD. The hub
genes identified in our network - such as NFKB1, RELA, SPP1, SP1, and HSPA2 - are central regulators in
these pathways, suggesting a direct mechanistic alignment between celastrol’s pharmacodynamics and the
molecular signatures disrupted in DMD. Celastrol also induces heat shock responses, enhances chaperone
expression [heat shock proteins (HSPs)], and modulates autophagy [127,128] . Given that impaired proteostasis
and defective muscle regeneration are hallmark features of DMD, these molecular effects provide a
biologically plausible rationale for celastrol’s therapeutic potential, particularly through modulating
SQSTM1, HSPA2, and GLS, which emerged as key nodes in our network analysis. Therefore, celastrol is