Blocking a Cell-Death Enzyme May Protect Hearing from Chemotherapy Damage

Blocking a Cell-Death Enzyme May Protect Hearing from Chemotherapy Damage

October 15, 2025 Author Summary 0

Why hearing loss happens with cisplatin

Cisplatin is a widely used anticancer drug, but it can permanently damage hearing. The article explains that cisplatin builds up in the inner ear—particularly in outer hair cells, spiral ganglion neurons, and the stria vascularis. In these tissues it drives oxidative stress, disrupts mitochondria, and ultimately kills the sensory hair cells that convert sound into electrical signals. Because these cells do not regenerate, many patients are left with lasting hearing loss or tinnitus. Attempts to curb this damage have often fallen short because protective agents can also blunt cisplatin’s tumor-killing effect. The goal is clear: protect the ear without protecting the cancer.

The idea: target PARP-1 and parthanatos

The study centers on poly(ADP-ribose) polymerase-1 (PARP-1). Normally, PARP-1 helps repair DNA, but when overactivated it can trigger a caspase-independent death route called parthanatos. In this pathway, apoptosis-inducing factor (AIF) moves from mitochondria into the nucleus and causes large-scale DNA fragmentation. The authors asked whether cisplatin overactivates PARP-1 in auditory cells and, if so, whether PJ34, a PARP-1 inhibitor, could interrupt this process.

What the researchers did

The team tested PJ34 in two systems that model cisplatin ototoxicity:

  • HEI-OC1 auditory cells exposed to cisplatin

  • Neonatal mouse cochlear explants cultured with cisplatin

To address the key safety question—would PJ34 protect tumors?—they also examined two ovarian cancer cell lines (HEY and TOV112D) treated with cisplatin, with or without PJ34.

Key findings at a glance

  • Auditory protection at low dose: PJ34 (especially at 2.5 μM) reduced cisplatin-induced apoptosis in HEI-OC1 cells and preserved hair-cell morphology in cochlear explants. Higher doses (5–10 μM) were less protective.

  • Tumor effects maintained (and sometimes enhanced): In HEY and TOV112D cells, adding PJ34 did not diminish cisplatin’s activity; in HEY cells it increased apoptosis compared with cisplatin alone.

  • Mechanism consistent with parthanatos: PJ34 did not lower cleaved caspase-3, pointing away from classic apoptosis. Instead, PJ34 reduced PARP-1 signal and limited AIF movement into the nucleus in auditory cells, aligning with a parthanatos-based mechanism.

  • Mitochondrial health improved: With PJ34, mitochondrial membrane potential recovered and mitochondrial ROS decreased after cisplatin exposure.

What’s novel here

The study links cisplatin ototoxicity to PARP-1–driven AIF translocation in auditory cells and shows that inhibiting PARP-1 can protect the ear while not shielding cancer cells. This dual result—otoprotection alongside preserved (or heightened) anticancer action—addresses a major barrier that has limited earlier protective strategies.

How to read the dose response

Protection was strongest at 2.5 μM PJ34 and waned at higher concentrations. The authors note that higher doses may engage off-target pathways, which could explain the non-linear response. The practical takeaway is that dose matters: a narrow, well-tolerated window may be required to maximize protection without unwanted effects.

Why this matters for researchers and clinicians

  • Mechanistic clarity: The data support a model in which cisplatin activates PARP-1 in auditory cells, leading to AIF-mediated death and mitochondrial dysfunction. Blocking PARP-1 interrupts this cascade.

  • Therapeutic direction: PARP-1 inhibition emerges as a testable strategy to prevent hearing loss during platinum chemotherapy. The observation that PJ34 does not impede cisplatin in ovarian cancer cells—and may enhance it in HEY cells—helps address oncologic safety concerns.

  • Experimental guidance: The study underscores the value of tracking AIF localization and mitochondrial readouts alongside standard apoptosis markers when evaluating otoprotective candidates.

Practical implications and next steps

For the field, this work suggests:

  • Target selection: Focusing on PARP-1 and the parthanatos axis is a promising route for otoprotection studies.

  • Dose optimization: Careful titration is critical; low micromolar PJ34 was beneficial, while higher doses were less so.

  • Translational checks: Further work in adult in vivo models and comparisons with other PARP inhibitors will be important to define feasibility, exposure in the inner ear, and durability of protection.

The Take-Home Message

Cisplatin can save lives but often harms hearing by damaging delicate inner-ear cells. This study shows that a small molecule, PJ34, blocks a DNA-repair enzyme (PARP-1) that, when overactive, triggers a destructive chain reaction in these cells. At the right dose, PJ34 helped inner-ear cells survive cisplatin and kept their mitochondria working, while it did not protect cancer cells from the drug. That combination—ear protection without tumor protection—makes PARP-1 inhibition a promising direction to explore.

Key messages

  • Problem: Cisplatin causes permanent hearing loss by injuring cochlear hair cells through oxidative and mitochondrial stress.

  • Mechanism: Overactivation of PARP-1 in auditory cells promotes AIF-mediated, caspase-independent cell death.

  • Solution tested: The PARP-1 inhibitor PJ34 protected auditory cells at low micromolar doses and improved mitochondrial measures.

  • Oncology safeguard: PJ34 did not weaken cisplatin against ovarian cancer cells and increased apoptosis in one line.

  • Implication: PARP-1 is a viable target for preventing cisplatin-related hearing loss without compromising anticancer efficacy.

 

The translation of the preceding English text in Chinese:

 

为什么顺铂会导致听力损失

顺铂是一种广泛使用的抗癌药物，但它可能永久性地损害听力。文章解释说，顺铂会在内耳中积聚——特别是在外毛细胞、螺旋神经元和血管纹中。在这些组织中，它会引发氧化应激、破坏线粒体，并最终杀死将声音信号转化为电信号的感觉毛细胞。由于这些细胞无法再生，许多患者因此出现永久性听力损失或耳鸣。
以往的保护尝试往往失败，因为某些保护剂也会削弱顺铂的抗肿瘤作用。研究的目标非常明确：在保护耳朵的同时，不保护癌细胞。

研究思路：靶向 PARP-1 与 parthanatos 细胞死亡途径

本研究的核心是 多(ADP-核糖)聚合酶-1（PARP-1）。在正常情况下，PARP-1 帮助修复 DNA，但当其过度激活时，会引发一种名为 parthanatos 的、与半胱天冬酶无关的细胞死亡途径。在这一过程中，促凋亡因子（AIF） 从线粒体转移到细胞核，引起大规模 DNA 断裂。
研究者提出问题：顺铂是否会在听觉细胞中过度激活 PARP-1？如果是这样，PJ34（一种 PARP-1 抑制剂）是否能够阻断这一过程？

研究方法

研究团队在两种模拟顺铂耳毒性的体系中测试了 PJ34 的作用：

  • HEI-OC1 听觉细胞 暴露于顺铂

  • 新生小鼠耳蜗外植体 在含顺铂的培养条件下培养

为了解决关键的安全性问题——PJ34 是否也会保护肿瘤细胞——研究者还检测了两种卵巢癌细胞系（HEY 和 TOV112D），分别在有或没有 PJ34 的情况下与顺铂联合处理。

主要发现一览

  • 低剂量下的听觉保护作用： PJ34（尤其是 2.5 微摩尔）能显著减少顺铂诱导的 HEI-OC1 细胞凋亡，并在耳蜗外植体中保持毛细胞结构。较高剂量（5–10 微摩尔）保护作用减弱。

  • 肿瘤效应保持甚至增强： 在 HEY 和 TOV112D 细胞中，加入 PJ34 并未削弱顺铂的活性；在 HEY 细胞中，PJ34 甚至增强了细胞凋亡。

  • 机制符合 parthanatos 模式： PJ34 未降低裂解型半胱天冬酶-3 的水平，说明其作用并非通过经典凋亡途径。相反，PJ34 降低了 PARP-1 信号，并限制了 AIF 向细胞核的转移，与 parthanatos 机制一致。

  • 线粒体功能改善： 加入 PJ34 后，顺铂处理引起的线粒体膜电位下降得到恢复，线粒体活性氧水平下降。

研究的新意

该研究将顺铂耳毒性与听觉细胞中 PARP-1 驱动的 AIF 转位 联系起来，并表明 抑制 PARP-1 可以保护耳蜗细胞而不影响肿瘤细胞。这种“双重效果”——既保护听力又保留（甚至增强）抗癌作用——克服了以往许多耳毒性防护策略面临的主要障碍。

剂量反应的解读

在 2.5 微摩尔 PJ34 时保护作用最强，随着浓度升高而减弱。作者指出，高剂量可能激活其他非靶向通路，从而解释了这种非线性反应。实际意义在于：剂量很关键——需要一个窄幅、耐受性好的剂量窗口，以最大化保护作用并避免副作用。

研究者与临床医生为何应关注

  • 机制清晰： 数据支持这样一个模型：顺铂在听觉细胞中激活 PARP-1，引发 AIF 介导的细胞死亡和线粒体功能障碍；阻断 PARP-1 可打断这一连锁反应。

  • 治疗方向： PARP-1 抑制成为一种可验证的策略，用于防止铂类化疗引起的听力损失。研究观察到 PJ34 不会削弱顺铂在卵巢癌细胞中的活性，甚至在 HEY 细胞中增强其效应，这有助于缓解肿瘤学安全性的担忧。

  • 实验参考： 研究强调在评估耳毒性保护候选药物时，应同时监测 AIF 定位 和 线粒体功能指标，与常规凋亡标志物配合使用。

实践意义与下一步工作

对该领域而言，这项研究表明：

  • 靶点选择： 聚焦于 PARP-1 与 parthanatos 通路是耳毒性防护研究的有前景方向。

  • 剂量优化： 精确滴定非常关键；低微摩尔浓度的 PJ34 有效，而更高剂量效果较差。

  • 转化验证： 未来应在成年动物体内模型中进一步研究，并与其他 PARP 抑制剂比较，以评估可行性、内耳暴露水平和保护持续性。

核心信息

顺铂能拯救生命，却常常损伤听力，因为它破坏了脆弱的内耳细胞。本研究显示，小分子 PJ34 能阻断一种 DNA 修复酶（PARP-1）的过度活化，从而阻止细胞内的破坏性连锁反应。在合适剂量下，PJ34 帮助内耳细胞在顺铂暴露下存活，并维持线粒体功能，同时并未保护肿瘤细胞。这种“保护耳朵而不保护肿瘤”的效果，使 PARP-1 抑制成为一个值得探索的新方向。

要点总结

  • 问题： 顺铂通过氧化应激和线粒体损伤破坏耳蜗毛细胞，导致永久性听力丧失。

  • 机制： 听觉细胞中 PARP-1 的过度激活促进了 AIF 介导的、非半胱天冬酶依赖性细胞死亡。

  • 解决方案： PARP-1 抑制剂 PJ34 在低微摩尔剂量下能保护听觉细胞，并改善线粒体指标。

  • 肿瘤学安全性： PJ34 未削弱顺铂在卵巢癌细胞中的作用，并在其中一株细胞中增强了凋亡。

  • 启示： PARP-1 是一个可行的靶点，可在不影响抗癌疗效的情况下预防顺铂相关听力损失。

Reference:

Huiming Nong, Xiru Zhang, Yingxue Yuan, Junhong Zhang, Jingyi Zhao, Zhixin Cao

PJ34 prevents cisplatin-induced hair cell loss via inhibition of PARP-1–AIF parthanatos.

Biomol Biomed [Internet]. 2025 Jun. 20 [cited 2025 Oct. 14];25(11):2537–2550.

Available from: https://www.bjbms.org/ojs/index.php/bjbms/article/view/12533

Additional information:

We invite submissions for our upcoming thematic issues, including:

More news: Blog

Editor: Merima Hadžić

Be the first to comment

Leave a Reply