The decline of progranulin expression in cochlear Microglia-Like Cells accelerates the progression of age-related hearing loss.

Accumulating evidence indicates that crosstalk between immune cells and intrinsic cochlear cells is critical for maintaining auditory homeostasis. However, the activation profile of cochlear microglia-like cells (MLCs) and their mechanistic role in age-related hearing loss (ARHL) remain poorly defined. Here, we show that MLCs are robustly activated in the cochlea of aged mice, and that pharmacologic depletion of cochlear MLCs significantly attenuates ARHL progression. To dissect the mechanisms underlying MLC-driven cochlear damage in ARHL, we leveraged the single-cell transcriptomic landscape of the aged mouse cochlea previously generated by our research group, and conducted the related functional validation. We identified prominent age-related alterations in cochlear MLCs, and revealed that AAV-mediated (via posterior semicircular canal microinjection) upregulation of progranulin (GRN) in MLCs mitigates aging-associated oxidative stress damage in the cochlea. Collectively, our work demonstrates that targeting GRN signaling in cochlear MLCs alleviates aging-related oxidative stress in the cochlea, and thereby delays ARHL progression.