Abstract

Age-related hearing loss (ARHL) is a growing global health concern due to its irreversibility and multifactorial pathogenesis. Epigenetic alterations are emerging as key drivers of aging, yet the mechanisms underlying their contribution to ARHL remain poorly understood. Here, we identified the histone H3 lysine 9 dimethylation (H3K9me2)-forkhead box G1 (FOXG1)-microRNA axis as a crucial regulator of auditory degeneration through modulation of autophagy. Using in vivo and in vitro D-galactose-induced aging models, we observed that H3K9me2 levels exhibited an inverse relationship with FOXG1 expression in cochlear hair cells. FOXG1 regulated autophagy by controlling autophagy-related microRNAs, thereby modulating reactive oxygen species accumulation and apoptosis in aging hair cells. Furthermore, a multi-omics approach delineated the broader FOXG1-mediated regulatory network driving ARHL. To our knowledge, this is the first study to comprehensively characterize the epigenetic regulation of autophagy by FOXG1 in ARHL, providing new mechanistic insights into cochlear hair cell aging and potential therapeutic targets.