Blocking a cell-death enzyme may help prevent chemotherapy-related hearing loss

Hearing loss as a complication of cancer treatment

Hearing loss is a common and often permanent side effect of cisplatin, a widely used chemotherapy drug for many solid tumors. Cisplatin accumulates in the inner ear, where it damages sensory hair cells and auditory neurons that are essential for converting sound into nerve signals. Because these cells do not regenerate, patients may experience lasting hearing loss or tinnitus, even after successful cancer treatment. Current strategies to prevent this damage are limited, in part because protective agents risk reducing cisplatin's effectiveness against tumors.

Why current approaches fall short

Most experimental otoprotective treatments aim to reduce oxidative stress or inflammation in the inner ear. However, many of these approaches have failed to translate clinically, either because protection is incomplete or because the same pathways are also involved in killing cancer cells. A key unmet need is to identify targets that are critical for hearing-cell damage but not required for cisplatin's anticancer action.

A focus on PARP-1–driven cell death

In this study, researchers examined the role of poly(ADP-ribose) polymerase-1 (PARP-1), an enzyme involved in DNA repair that can trigger a caspase-independent form of cell death known as parthanatos when overactivated. The team investigated whether cisplatin activates PARP-1 in auditory cells and whether inhibiting this enzyme could interrupt the cell-death process.

How the study was conducted

The researchers tested the PARP-1 inhibitor PJ34 in cultured auditory cells and in mouse cochlear tissue exposed to cisplatin. To assess whether blocking PARP-1 might interfere with cancer treatment, they also evaluated the effects of PJ34 in combination with cisplatin in two ovarian cancer cell lines.

Key findings

The study showed that low-dose PJ34 reduced cisplatin-induced damage in auditory cells and preserved the structure of sensory hair cells in cochlear tissue. PJ34 improved mitochondrial function and reduced oxidative stress following cisplatin exposure. The protective effect was linked to reduced PARP-1 activity and limited movement of apoptosis-inducing factor (AIF) into the nucleus, supporting a parthanatos-based mechanism rather than classical apoptosis.

Importantly, PJ34 did not weaken cisplatin's anticancer effects in ovarian cancer cells. In one of the tested cell lines, combining PJ34 with cisplatin increased tumor cell death compared with cisplatin alone.

Why dose matters

Protection of auditory cells was strongest at low micromolar concentrations of PJ34 and declined at higher doses. This non-linear response suggests that careful dose optimization will be essential and that off-target effects may emerge at higher concentrations.

Implications for understanding hearing loss

The findings provide mechanistic insight into how cisplatin damages the inner ear, identifying PARP-1 activation and AIF-mediated cell death as central drivers of auditory cell loss. This advances understanding of the molecular pathways underlying chemotherapy-related hearing impairment.

Limitations and next steps

The study was conducted in cell and tissue models, and further work in adult animal models will be needed to assess drug delivery to the inner ear, long-term protection, and safety. Future studies will also need to compare PJ34 with other PARP inhibitors and evaluate whether this strategy can be translated to clinical use.

Why this research matters

By showing that inhibition of PARP-1 can protect hearing cells without shielding cancer cells, this study highlights a potential path toward preventing cisplatin-related hearing loss while preserving the effectiveness of cancer treatment.

More information:

Huiming Nong et al, PJ34 prevents cisplatin-induced hair cell loss via inhibition of PARP-1–AIF parthanatos. Biomol Biomed [Internet]. 2025 Jun. 20 [cited 2025 Dec. 12];25(11):2537–2550.

Available from: https://doi.org/10.17305/bb.2025.12533

Journal information: Biomolecules and Biomedicine

Provided by: Association of Basic Medical Sciences of FBIH

Provided by Association of Basic Medical Sciences of FBIH