Restoring Iron Homeostasis via Smoothened Inhibition: A Novel Strategy Against Hearing Loss

ABSTRACT Sensorineural hearing loss (SNHL) induced by noise or aminoglycoside antibiotics is a significant public health concern without any FDA‐approved pharmaceutical therapies. Dysregulation of iron homeostasis and its subsequently induced ferroptosis has increasingly been identified as a key mechanism underlying cochlear hair cell (HC) damage. Nevertheless, the therapeutic targets for restoring iron balance for hearing protection remain poorly investigated. In this study, we uncover a previously unrecognized role of the SMO pathway in regulating iron homeostasis. SMO expression was rapidly upregulated and activated in HCs following injury. Both genetic ablation of Smo and pharmacological inhibition of SMO reduced iron accumulation and lipid peroxidation, promoting HC survival and preserving auditory function in mouse models of ototoxic‐ and noise‐induced hearing loss. Mechanistically, SMO inhibition suppressed ATF2 phosphorylation, resulting in downregulation of IRP1, which decreased iron accumulation via downregulation of Tfrc and upregulation of Fpn , ultimately protecting HCs from ferroptosis. Notably, treatment with the SMO inhibitor SANT‐1 nearly restored auditory thresholds to baseline levels in mice subjected to ototoxic injury. Our findings identify the SMO–ATF2–IRP1–FPN/TFRC axis as a central regulator of cochlear iron homeostasis and propose SMO inhibition as a promising therapeutic strategy for SNHL through precise modulation of iron metabolism.