Cisplatin, a potent chemotherapeutic drug, induces ototoxicity, which limits its clinical utility. Cisplatin-induced oxidative stress plays a causal role in cochlear apoptosis while the consequent nitrative stress leads to the nitration of LIM domain only 4 (LMO4), a transcriptional regulator, and decreases its cochlear expression levels. Here, we show a direct link between cochlear LMO4 and cisplatin-induced hearing loss by employing a Lmo4 conditional knockout mouse model (Lmo4^lox/lox; Gfi1^Cre/+). Hair cell-specific deletion of Lmo4 did not alter cochlear morphology or affect hearing thresholds and otoacoustic emissions, in the absence of apoptotic stimuli. Cisplatin treatment significantly elevated the auditory brainstem response thresholds of conditional knockouts, across all frequencies. Moreover, deletion of Lmo4 compromised the activation of STAT3, a downstream target that regulates anti-apoptotic machinery. Immunostaining indicated that the expression of phosphorylated STAT3 was significantly decreased while the expression of activated caspase 3 was significantly increased in Lmo4 deficient hair cells, post-cisplatin treatment. These findings suggest an otoprotective role of LMO4 as cisplatin-induced decrease in cochlear LMO4 could compromise the LMO4/STAT3 cellular defense mechanism to induce ototoxicity.

顺铂是一种强效化疗药物，会引起耳毒性，这限制了其临床应用。顺铂诱导的氧化应激在耳蜗凋亡中起因果作用，而随后的硝化应激导致转录调节因子 LIM domain only 4 (LMO4) 的硝化，并降低其耳蜗表达水平。在这里，我们通过使用Lmo4条件性敲除小鼠模型 ( Lmo4 ^lox/lox ; Gfi1 ^Cre/+ )显示了耳蜗 LMO4 与顺铂引起的听力损失之间的直接联系。Lmo4的毛细胞特异性缺失在没有凋亡刺激的情况下，不会改变耳蜗形态或影响听力阈值和耳声发射。顺铂治疗在所有频率上显着提高了条件性敲除的听觉脑干反应阈值。此外，Lmo4的缺失损害了 STAT3 的激活，STAT3 是调节抗凋亡机制的下游靶标。免疫染色表明，顺铂处理后Lmo4缺陷毛细胞中磷酸化 STAT3 的表达显着降低，而活化的半胱天冬酶 3 的表达显着增加。这些发现表明 LMO4 的耳保护作用，因为顺铂诱导的耳蜗 LMO4 减少可能会损害 LMO4/STAT3 细胞防御机制以诱导耳毒性。