Metabolic-dysfunction-associated steatohepatitis impairs cochlear integrity and delays auditory recovery after noise trauma

Chronic hearing impairment represents a major global health burden, profoundly diminishing quality of life due to its association with depression and cognitive decline. Recent studies have identified metabolic-dysfunction-associated steatohepatitis (MASH) as an independent systemic risk factor for accelerated hearing loss, implicating a functional liver–inner ear axis. However, the molecular and vascular mechanisms through which MASH-induced systemic inflammation compromises cochlear integrity remain uncertain. We investigated the impact of MASH on cochlear pathology and auditory function. MASH was induced in 8-week-old male BALB/c mice by feeding a methionine–choline-deficient (MCD) diet for 4 weeks. After this induction period, the mice were exposed to acoustic trauma and maintained on the same diet for an additional 2 weeks. Systemic and cochlear evaluations were performed to assess the impact of MASH on auditory function and related physiological alterations. The MCD diet induced severe hepatic steatosis and lobular inflammation, accompanied by cochlear stria vascularis (SV) hyperpermeability and inflammation characterized by elevated interleukin (IL)-1β and lipocalin-2 (LCN2), without overt hearing loss or hair cell damage. Following noise exposure, MCD-fed mice demonstrated significantly delayed auditory recovery compared to chow-fed controls. This delay was associated with cochlear synaptopathy (CtBP2 degeneration), exacerbated BLB dysfunction, and ultrastructural alterations in endothelial cells, pericytes, and perivascular macrophages within the stria vascularis. PDGFRβ expression was significantly reduced, while proinflammatory mediators (IL-6, IL-1β, and LCN2) were upregulated, suggesting concurrent vascular injury and inflammatory activation. These findings demonstrate that MASH sensitizes the cochlea to noise-induced injury through disruption of the BLB and sustained inflammation, providing a preclinical model and mechanistic insight into the link between MASH and hearing loss. People with metabolic liver disease are known to have a higher risk of hearing problems, but it has not been clear why. In this study, we discovered a biological link between metabolic dysfunction–associated steatohepatitis (MASH) and increased vulnerability of the inner ear to noise. Using a mouse model fed a methionine–choline–deficient (MCD) diet, we found that liver inflammation and fat accumulation weaken the blood–labyrinth barrier (BLB)—a structure that protects the sensory cells of the inner ear—without causing immediate hearing loss. Although hearing thresholds appeared normal under quiet conditions, these mice showed subtle vascular changes in the cochlea and a delayed recovery after noise exposure. We identified a liver-derived protein called lipocalin-2 (LCN2) as a key circulating factor responsible for this effect. Elevated LCN2 levels disrupted the microvasculature of the stria vascularis by damaging endothelial and supporting pericyte cells, leading to increased vascular leakage and amplification of local inflammatory responses. Moreover, LCN2 interacted with inflammatory molecules interleukin-1β (IL-1β) and interleukin-6 (IL-6) to form a self-reinforcing inflammatory loop that prolonged cochlear injury and slowed hearing recovery. These findings show that metabolic liver disease can “prime” the inner ear, making it more susceptible to environmental stress such as loud noise. Overall, our results highlight a new liver–inner ear axis, revealing how chronic liver inflammation can affect distant sensory organs. This study suggests that maintaining metabolic and vascular health is critical for protecting hearing, and it identifies LCN2 and the BLB as potential therapeutic targets for preventing or reducing hearing loss associated with metabolic diseases.