Histamine deficiency exacerbates cisplatin-induced ferroptosis in cochlea hair cells of HDC knockout mice

Cisplatin (CDDP) is extensively utilized in the management of diverse types of cancers, but its ototoxicity cannot be ignored, and clinical interventions are not ideal. Histidine decarboxylase (HDC) is the exclusive enzyme for histamine synthesis. Anti-histamine receptor drugs are ubiquitously employed in the therapeutics of allergies and gastrointestinal diseases. Yet, the specific role of histamine and its signaling in the inner ear is not fully understood. This study utilized cisplatin treated mice and HEI-OC1 auditory hair cell line to establish a cisplatin-induced ototoxicity (CIO) model. Histidine decarboxylase knockout (HDC^−/−) mice and histamine receptor 1 (H₁R) antagonist were utilized to investigate the influence of HDC/histamine/H₁R signaling on ototoxicity. The results identified HDC and H₁R expression in mouse hair cells. Transcriptomics indicated that the expression levels of oxidative stress-related genes in the cochlea of HDC^−/− mice increased. Furthermore, histamine deficiency or suppression of H₁R signaling accelerated HC ferroptosis, a pivotal factor underlying the aggravation of CIO in vivo and in vitro, conversely, the supplementation of exogenous histamine reversed these deleterious effects. Mechanistically, this study revealed that the malfunction of HDC/histamine/H₁R signaling induced upregulation of NRF2 expression, accompanied by the upregulation of ACSL4 and downregulation of GPX4 expression, which are major regulatory factors of ferroptosis. In summary, histamine deficiency may induce hair cell death by regulating the H₁R pathway and exacerbate CIO. Our findings have indicated a potential therapeutic target for CIO.