TNFAIP8L2 maintains Hair cell function and Regulates Age-related hearing loss via mTORC1 Signaling.

Age-related hearing loss (ARHL) is one of the most prevalent and complex disorders. Our previous study demonstrated that abnormal activation of mTORC1 signaling in the cochlear neurosensory epithelium (NSE) causes auditory hair cell damage and contributes to ARHL. However, the underlying mechanism of mTORC1 activation remains unclear. In this study, we identified TNF-alpha-induced protein 8-like 2 (TNFAIP8L2), an immune regulatory gene, as a potential candidate. To elucidate the effect of TNFAIP8L2 on mTORC1 signaling in the NSE and on hearing function, we generated a Tnfaip8l2-deficient (Tnfaip8l2^-/-) mouse model. We discovered that Tnfaip8l2-deficiency led to features of oxidative stress in cochlear hair cells and age-related hearing degeneration, exhibiting a similar phenotype to the mTORC1-overactivated Tsc1-cKO mice described previously. Furthermore, rapamycin, a well-known mTORC1 inhibitor, significantly mitigated the hearing dysfunction caused by Tnfaip8l2-deficiency. Mechanistically, we found that TNFAIP8L2 regulates mTORC1 signaling by simultaneously inhibiting the GTPase activity of RHEB and RAC1. Notably, both RHEB and RAC1 inhibitors alleviated the hearing phenotype observed in Tnfaip8l2^-/- mice by inhibiting mTORC1 signaling. Collectively, our results provide insights into the activation of the mTORC1 pathway in aged mouse cochleae and positions TNFAIP8L2 as a valuable theoretical strategy.