Multi-omics Analysis Reveals the Role of lncRNAs and Peptides in the Age-related Hearing Loss

The pathogenesis of age-related hearing loss (ARHL), especially the role of long non-coding RNAs (lncRNAs) and their encoded peptides, remains incompletely understood. This study aimed to characterize expression changes in lncRNAs and peptides in the cochleae of ARHL mice and explore the potential functions of lncRNA-encoded peptides via multi- -omics analysis.

C57BL/6J mice were used to establish the ARHL model. The molecular expression profiles of cochlear tissues from normal and ARHL mice were synthesized by lncRNA sequencing, peptidomics, and bioinformatics.

Compared with the control group, a total of 789 differentially expressed lncRNAs and 466 differentially expressed peptides were identified in the ARHL group. Functional enrichment analysis revealed their association with key pathways, including ion transport, calcium signaling, the TCA cycle, and cytoskeleton regulation, indicating broad molecular dysregulation in the aging cochlea. Notably, 64 differentially expressed lncRNAs showed high translational potential, yielding 107 novel lncRNA-encoded peptides. These were mainly short peptides, some with stabilizing hydrophobic properties suited for membrane interactions, and enriched in domains like Pkinase and C2, suggesting involvement in signal transduction.

These results emphasized that lncRNA-encoded peptides were novel regulators of ARHL, potentially regulating calcium homeostasis and mitochondrial function. The overlap of pathways such as the cytoskeleton and fatty acid metabolism indicated that the lncRNA-peptide axis drove auditory decline, providing institutional insights into the epigenetic basis of ARHL.

Our findings suggest that lncRNA-encoded peptides are a novel class of regulatory molecules involved in the complex pathogenesis of ARHL, highlighting them as promising targets for future therapeutic strategies.