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INNOSC Theranostics and
Pharmacological Sciences Cholesteatoma enrichment pathways for drug repurposing

cultures , and direct expression studies on cholesteatoma can lead to the proposal of various other medications such
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tissues 20-23 have been utilized to decipher the complex as duvelisib, an anti-PIK3 medication. This inhibitor has
molecular interplay of proinflammatory pathways in been suggested previously, since the PI3K-Akt signaling
3
relation to metalloproteins, osteoclasts activation, and pathway enriched by our method has also been proposed
bone resorption. Most of the above indicative references in cholesteatoma pathogenesis in a separate study focusing
conclude that various MMPs are related to disease only on molecules involved in this pathway. 28
aggressiveness or recurrence. There are indications of This information is particularly valuable given the limited
dysregulation of local immune status in cholesteatoma, as research funding allocated to cholesteatoma. The discovery
suggested by the expression studies of several ILs and other of a dedicated medical treatment for cholesteatoma
cytokines 24,25 or the study of various signaling pathways within the next few years is unlikely. However, drug
such as those involving triggering receptor expressed on repurposing offers an efficient and cost-effective pathway
myeloid cells-2 and toll-like receptor 4. Nevertheless, a toward this goal. Relying on drug repositioning for the
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partial understanding of the proinflammatory mediators development of cholesteatoma management strategies is a
and MMPs in bone resorption has been achieved, pragmatic approach, considering the challenging research
as indicated by, for example, the conflicting results landscape.
published regarding the promising role of the RANKL/
orthopantomogram pathway. 26,27 Furthermore, some of the medications identified in our
analysis could potentially be applied topically during initial
In addition, our approach enriched less well-studied treatment to assess their impact on reducing cholesteatoma
pathways of cholesteatoma pathogenesis, such as apoptosis recurrence. For example, incorporating zinc into materials
and the PI3K-AKT pathways and provided some less- used in cholesteatoma procedures, such as bone-alive
expected insights, such as the finding of interactions at or gelfoam, could serve as a practical trial to evaluate its
vascular wall. There is an increasing body of evidence that effectiveness in reducing recurrence rates.
epithelial keratinocytes in cholesteatoma are protected
against apoptosis. 28-30 There are also some indications of the Finally, our study highlighted the utility of FLAME,
presence of drivers of angiogenesis, although the exact a validated open-source program capable of integrating
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role of these factors in the perimatrix of cholesteatoma is complex genetic data. While FLAME’s application extends
largely unknown. The notable aspect of these studies is that to various diseases, it particularly proves invaluable in the
they provide a molecular framework and do not dispute context of cholesteatoma, as demonstrated in our research.
common mechanical theories of cholesteatoma formation, This tool has the potential to advance our understanding
such as the retraction pocket mechanical theory. of the genetic underpinnings of the pathological condition
and may have broader applications in medical research
Our analysis also led to the identification of medications beyond cholesteatoma.
that either have previously been suggested for cholesteatoma
treatment, such as anti-tumor necrosis factor α (TNFα), 5. Conclusion
or are unexpected, such as zinc or heparin. Notably, there
is a case report suggesting the potential effectiveness of Functional enrichment analyses are particularly promising
anti-TNFα in cholesteatoma management. TNFα, a for underfunded research areas, as they can suggest
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multifunctional proinflammatory cytokine implicated also potential avenues for drug repurposing. Our study
in lipid metabolism, coagulation, insulin resistance, and highlights the value of high-throughput approaches
endothelial function, seems to be involved in several of the and the integration of bioinformatic tools in elucidating
proposed molecular pathways extracted from our analysis. cholesteatoma pathogenesis, both by confirming known
pathways and identifying novel therapeutic targets.
In addition to these findings, our analysis proposed
other substances, such as zinc and marimastat, which hold Acknowledgment
promise in cholesteatoma treatment. Of note is that the We would like to thank G. Pavlopoulos for his valuable
bioinformatic programs utilized here for the discovery of comments on FLAME bioinformatic tool.
potential medical treatments are well-known and freely
available, but they do not utilize artificial intelligence for Funding
the elaboration of the expanding knowledge at molecular
level. At present, several companies are developing their None.
own proprietary algorithms for drug repurposing and have Conflict of interest
already provided important results in other diseases. Here,
a primary reading of the suggested molecular pathways The authors declare no conflict of interest.

Volume 8 Issue 3 (2025) 110 doi: 10.36922/itps.2571