Mutations in oxysterol-binding protein like 2 (OSBPL2) were identified to be responsible for autosomal dominant non-syndromic hearing loss (DFNA, OMIM: 616340) (Xing et al., 2015). As a member of the oxysterol-binding proteins (OSBP) related proteins family (OSBP/ORPs), OSBPL2 is known as a critical sterol receptor and participates multiple bioprocess, including lipid metabolism, vesicle transport, signal transduction, autophagy and actin-dependent cytoskeleton regulation (Arora et al., 2022; Tan and Finkel, 2022). However, the pathogenic mechanism of OSBPL2 mutations in auditory disorder has not been thoroughly clarified. Our previous study revealed that OSBPL2 was localized in the structures of mouse cochlear spiral duct, including basal membrane (BM), spiral ganglion (SG) and stria vascularis (SV), in which OSBPL2 could play an important role in the maintenance of auditory function (Xing et al., 2015). The OSBPL2-disrupted pigs exhibited progressive hearing loss characterized by the degeneration and apoptosis of cochlear hair cells (HCs) and morphological abnormalities in HC stereocilia, along with hypercholesterolemia (Yao et al., 2019). A recent study reported that mutant OSBPL2 accumulated intracellularly and bound to macroautophagy/autophagy proteins, causing defective endolysosomal homeostasis and impaired autophagy (Koh et al., 2022). Our previous study revealed the increased levels of cholesterol biosynthesis, ROS production and the mitochondrial damage in Osbpl2-deficient auditory cells (Wang et al., 2019). OSBPL2 deficiency led to ciliary defects and abnormal Shh signaling transduction in auditory cells (Shi et al., 2022). These findings indicate that there could be multiple pathogenic mechanisms of OSBPL2 deficiency in specific context of sub-tissue or cell types.

The cochlear SV is the upper layer of the spiral ligament of the cochlear duct that contains numerous small blood vessels and is composed of marginal, intermediate and basal cells, is essential for the generation and maintenance of the ion composition and homeostasis of cochlear endolymph (Zdebik et al., 2009). SV lesion could occur due to aging, ototoxic drugs, noise exposure, inflammation, and genetic disease, which leads to progressive and irreversible hearing loss (Shin et al., 2019; Thulasiram et al., 2022). The blood-labyrinth barrier (BLB), a specialized capillary network in the middle cell layer of the SV, regulates the exchange of ions, molecules and other substances from the blood into the endolymph, and it consists of endothelial cells, pericytes (PCs), basement membrane and perivascular resident macrophage-like melanocytes (PVM/Ms), which are structurally and functionally similar to the blood-brain barrier (BBB) (Cosentino et al., 2024; Nyberg et al., 2019). It is known that disruption of the BBB is closely associated with the pathogenesis of multiple degenerative disorders, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and multiple sclerosis (Nguyen et al., 2021; Sweeney et al., 2019; Zlokovic, 2008). It has been found that the abnormal cell number and morphology of PCs and PVM/Ms, as well as Na+, K+-ATPase damage could disrupt BLB integrity and increase its permeability (Gu et al., 2022; Shi, 2016; Zhang et al., 2012). In addition, the function of the BLB also relies on the structural integrity of the endothelial cells, which is maintained by tight junctions (TJs) within the microvascular endothelium (Neng et al., 2013; Zhang et al., 2013). These findings indicate that the abnormal ultrastructural change of BLB could be responsible for SV lesion and lead to auditory dysfunction.

In this study, we aimed to investigate the impact of OSBPL2 deficiency on the function of the SV and explore the underlying mechanisms. Our findings contributed to deeply understanding the biological function of OSBPL2 and the pathogenic mechanisms of OSBPL2 deficiency implicated in DFNA.