Short-chain fatty acids significantly alleviate cisplatin induced sensory cell damage and hearing loss by maintaining the expression of MUTYH

Abstract Cisplatin is a potent, broad-spectrum chemotherapeutic agent widely used against multiple malignancies, yet its clinical utility is substantially restricted by dose-limiting adverse effects dominated by nephrotoxicity and ototoxicity. Although cisplatin-induced ototoxicity has been recognized for decades, the precise molecular cascades triggering cisplatin-evoked permanent hearing impairment remain incompletely defined. Therefore, in-depth investigation into the molecular mechanisms of cisplatin-induced ototoxicity and the development of effective prevention strategies represent key scientific issues. Herein, we constructed a chronic cisplatin-exposed animal model and verified prominent pathological features encompassing excessive DNA damage and mitochondrial dysfunction, paralleled by marked downregulation of the DNA repair enzyme MUTYH. Follow-up in vitro assays validated that overexpression of MUTYH significantly alleviated cisplatin-induced ROS accumulation, cell apoptosis, and DNA damage, suggesting that downregulation of MUTYH may be a key molecular event in cisplatin-induced ototoxicity. Notably, exogenous short-chain fatty acid supplementation robustly rescued cisplatin-induced sensory cell loss and hearing loss, concurrent with restored MUTYH abundance. Collectively, our findings reveal that short-chain fatty acids protect cochlear sensory cells from cisplatin-initiated DNA damage via sustaining MUTYH expression, thereby preserving auditory function. As indispensable gut microbial metabolites in humans, short-chain fatty acids supplementation holds promising translational potential as a clinically viable regimen to counteract cisplatin-associated ototoxicity.