Key molecular and cellular mechanisms underlying cholesteatoma pathogenesis.
| Pathobiological axis | Representative molecules/Pathways | Functional outcome/pathophysiological role | Key references |
|---|---|---|---|
| Chronic inflammation and immune signaling | NF-κB, MAPK, JAK–STAT, TLR4, TNF-α, IL-1β, IL-6, IL-8 | Sustains cytokine-driven inflammation, enhances keratinocyte proliferation, and promotes osteoclastogenic signaling | [6, 10, 12] |
| Proteolytic matrix remodeling | MMP-2, MMP-8, MMP-9, MMP-14, cathepsins | Degrades extracellular matrix and bone tissue, facilitating epithelial invasion and ossicular erosion | [7, 13, 14, 33] |
| Osteoclast-driven bone resorption | RANKL, OPG, activin A, PTHrP | Promotes osteoclast differentiation and activity, driving localized bone destruction | [11, 15] |
| Epithelial plasticity and partial EMT | OPN–CD44–AKT, ZEB2 | Enables keratinocyte survival, migration, and matrix interaction | [8, 16] |
| Microbiome and biofilm persistence | Microbial biofilms, TLR activation, quorum-sensing, dysbiosis | Maintains chronic inflammation via persistent innate immune activation and antimicrobial resistance | [17–19] |
| Oxidative stress | ROS, MPO | Amplifies inflammatory signaling, protease induction, and DNA/RNA oxidative damage | [8, 20] |
| Epigenetic and RNA modifications | DNA methylation, histone acetylation (H3K27ac), m6A-modified circular RNAs | Alters gene expression programs governing proliferation, inflammation, and ECM remodeling | [21, 22] |
| miRNA dysregulation | miR-223-3p, miR-142-5p, miR-21-5p, exosomal miRNAs | Modulates inflammatory signaling, osteoclastogenesis, and intercellular communication; potential biomarkers | [23–25] |
| Immune cell infiltration and phenotypes | M1/M2 macrophage polarization (CD80+/CD163+), T-cell subsets, mast cells | Shapes inflammatory milieu, influences matrix degradation, and contributes to bone erosion and fibrosis | [26, 27] |
OPG: osteoprotegerin; PTHrP: parathyroid hormone-related protein; OPN: osteopontin; MPO: myeloperoxidase; m6A: N6-methyladenosine; ZEB2: zinc finger E-box binding homeobox 2.