Hyperbilirubinemia (HB) is a key risk factor for hearing loss in neonates, particularly premature infants. Here, we report that bilirubin (BIL)-dependent cell death in the auditory brainstem of neonatal mice of both sexes is significantly attenuated by ZD7288, a blocker for hyperpolarization-activated cyclic nucleotide-gated (HCN) channel-mediated current (I_h), or by genetic deletion of HCN1. GABAergic inhibitory interneurons predominantly express HCN1, on which BIL selectively acts to increase their intrinsic excitability and mortality by enhancing HCN1 activity and Ca²⁺-dependent membrane targeting. Chronic BIL elevation in neonatal mice in vivo increases the fraction of spontaneously active interneurons and their firing frequency, I_h, and death, compromising audition at the young adult stage in HCN1^+/+, but not in HCN1^–/– genotype. We conclude that HB preferentially targets HCN1 to injure inhibitory interneurons, fueling a feedforward loop in which lessening inhibition cascades hyperexcitability, Ca²⁺ overload, neuronal death, and auditory impairments. These findings rationalize HCN1 as a potential target for managing HB encephalopathy.

高胆红素血症 （HB） 是新生儿，尤其是早产儿听力损失的关键危险因素。在这里，我们报道了 ZD7288 显着减弱了两性新生小鼠听觉脑干中胆红素 （BIL） 依赖性细胞死亡，ZD7288 是超极化激活的环核苷酸门控 （HCN） 通道介导的电流 （I _h） 的阻断剂，或通过 HCN1 的基因缺失。GABA 能抑制性中间神经元主要表达 HCN1，BIL 通过增强 HCN1 活性和 Ca²⁺ 依赖性膜靶向选择性地发挥作用，增加其内在兴奋性和死亡率。新生小鼠体内慢性 BIL 升高增加了自发活跃的中间神经元的分数及其发射频率、I_h 和死亡，影响了 HCN1 ^{+ / +} 青年阶段的听觉，但不会影响 HCN1 ^–/– 基因型的听觉。我们得出结论，HB 优先靶向 HCN1 以损伤抑制性中间神经元，从而推动前馈回路，其中抑制减少级联反应过度兴奋、Ca²⁺ 过载、神经元死亡和听觉障碍。这些发现使 HCN1 成为治疗 HB 脑病的潜在靶点。