Ototoxicity-induced c-Fos activation underlies the regenerative capacity of the vestibular sensory epithelia.

The mammalian inner ear exhibits a striking dichotomy in regenerative capacity: while vestibular hair cells retain limited ability to regenerate, cochlear hair cells permanently lose this potential after birth. Exploiting this disparity, we employed single-cell comparative transcriptomics combined with lineage tracing to identify c-Fos as a critical early responder selectively activated in the vestibular epithelium following ototoxic injury. Transcriptomic and chromatin profiling revealed that c-Fos initiates regenerative reprogramming by transcriptionally priming Atoh1, the master regulator of hair cell fate, while synergizing with the Wnt and Notch pathways to balance progenitor proliferation and trans-differentiation. Functional validation showed that c-Fos overexpression significantly promoted vestibular hair cell regeneration and restored balance function in adult mice. Our findings establish c-Fos as a molecular switch bridging acute injury responses to tissue repair and highlight its potential as a therapeutic target for vestibular rehabilitation.