Role of Epigenetics in the Pathogenesis of Acquired Cholesteatoma—A State of the Art Review

Objective: Cholesteatoma is a leading cause of hearing loss. There is evidence that cholesteatoma has a heritable component. Treatment includes multiple and aggressive surgeries. Research on non-surgical treatments is crucial to improve outcomes. Epigenetic changes can be inherited or environmentally acquired. These changes are pharmaceutically reversible, and epigenetic research has led to the FDA approval of several agents used in cancer treatment. Our goal was to review the literature investigating epigenetics in cholesteatoma to understand its role in pathogenesis and identify targets for epigenetic agents. Data Sources: PRIMSA 2020 statement was used as the framework. Cochrane, Embase, PubMed/Medline, Scopus, and Web of Science were searched for keywords related to epigenetics and middle ear cholesteatoma until October 2025. Review Methods: Two reviewers (PA and AC) screened the records. Disputed records were resolved by a senior author (TB). 769 records were retrieved, 26 deemed eligible for inclusion. Results: Most studies were from China. Only a few included pediatric subjects. Most investigated non-coding RNAs as the epigenetic mechanism; although one study investigated histone modifications and two investigated RNA methylation. Overall, there was differential expression of several noncoding RNAs in cholesteatoma. These noncoding RNAs are involved in regulation of cytokines and molecules that affect proliferation and apoptosis. Conclusions: Epigenetic changes may contribute to the pathogenesis of cholesteatoma through dysregulation of several biological pathways. Further studies identifying specific targets such as miRNA-21 and those investigating DNA methylation and histone modifications have the potential to develop biomarkers and targeted pharmaceutical agents for the treatment of cholesteatoma.