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INNOSC Theranostics and
Pharmacological Sciences Cholesteatoma enrichment pathways for drug repurposing

intervention remains the primary strategy for managing pipelines, and merging and prioritizing results through
cholesteatoma, but it is far from ideal. Recurrence rates, sophisticated interactive visualizations. In our study,
soaring up to 40%, continue to be a challenging problem FLAME was utilized to correlate gene lists at a network
and the invasive nature of surgery places the structures of level, leveraging resources such as aGOtool, g:Profiler,
the temporal bone at risk. This underscores the pressing WebGestalt, and EnrichR. Common enrichment pathways
1-3
need for a more effective, non-invasive medical approach between the high-throughput cholesteatoma genetic
to cholesteatoma management. studies were retrieved by utilizing the aforementioned
The pharmaceutical industry’s prioritization of drug tools. The number of times a pathway was found, and the
development has left cholesteatoma largely overlooked. higher enrichment scores were extracted. In addition, the
To date, there are no investigational drugs specifically option to enrich the provided gene lists from DrugBank
designed for this condition. However, signs of hope and gene list automatically derived for you (GLAD4U)
emerge through the field of drug repurposing, also known drug annotations were chosen to find potential medical
as drug repositioning. This innovative approach seeks to treatment options. The statistical significance of the
identify new therapeutic applications for existing drugs, combined results is estimated by applying Fisher’s
2
whether approved for other indications or previously combined probability test represented by X and combined
failed in clinical trials. By investigating this unexplored P-value metrics for each enrichment term identified by two
4
opportunity in the field of pharmaceuticals, we may or more tools.
uncover a medical treatment that could revolutionize Studies on specific genetic factors and pathways were
cholesteatoma management. excluded from the analysis since the aim of this in silico
Even though the cholesteatoma’s pathophysiology analysis is to enrich current knowledge, or in other words,
remains largely unclear, a surge in genetic research, to suggest possible new molecular targets in cholesteatoma
driven by high-throughput techniques, has yielded a research and treatment. 8
wealth of data. Thousands of gene expression profiles 3. Results
and non-coding microRNAs have been studied. Yet, the
5
underlying mechanisms of cholesteatoma development Of the nine high-throughput genetic studies that were
and progression remain largely unknown. At this point, identified, extended gene lists were available in six. 8-13 In
1,2
bioinformatics, based on the advances of computer, have three studies, 14-16 a full list of genetic factors could not be
the potential to make sense of all this genetic information. retrieved in the published paper and after contacting the

In this regard, this study aims to utilize advanced corresponding author.
bioinformatics to carefully examine the extensive Overlapping enriched that can be found in at least two
genetic data accessible for cholesteatoma. By thoroughly studies is shown in Table 1.
exploring this abundance of information, our goal is to Drugs or substances proposed following this in silico
identify the likely molecular pathways responsible for analysis as potential robust modulators of the enriched
cholesteatoma formation, progression, and recurrence. metabolic pathways are shown in Table 2.
Armed with these insights, we seek to propose the
repurposing of drugs associated with these identified 4. Discussion
pathways. This interdisciplinary approach merges genetics,
bioinformatics, and pharmacology, offering a promising In the present study, we focused on utilizing high-
avenue for cholesteatoma treatment innovation. throughput studies as they provide a multifaceted set of
genetic data. This approach was chosen because studies
2. Methods analyzing only a few genes may introduce selection bias
and may not require advanced bioinformatic techniques to
Published high-throughput genetics studies were reveal potential pathways. By employing high-throughput
searched in the PubMed database. Genes or other genetic
factors that can be retrieved by these publications and data, we aimed to reduce the risk of bias and gain a more
their corresponding databases were then introduced in complete understanding of the genetic factors associated
functional and literature enrichment analysis of multiple with cholesteatoma.
sets (FLAME), a novel validated web bioinformatics The limitation of this analysis is that we primarily relied
6,7
platform, which is freely available to public. FLAME on expression studies. While these studies offer valuable
excels in the simplicity of use, providing extensive flexibility insights, they cannot definitively establish whether the
in importing and managing multiple lists, executing altered gene expression is a primary cause or a secondary
advanced state-of-the-art functional enrichment analysis effect of cholesteatoma. Consequently, it remains uncertain

Volume 8 Issue 3 (2025) 108 doi: 10.36922/itps.2571