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Pharmacological Inhibition of JAK/STAT-IL2 Axis Alleviated Cisplatin-Induced Ototoxicity

Shimei Zheng1,2, Chang Liu3, Jiahuan Li1,2

  • 1ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, 83 Fenyang Road, Shanghai, 200031, China.

Molecular Neurobiology
|November 19, 2025
PubMed

Insights

This study shows that inhibiting the JAK/STAT pathway protects hearing cells from damage. Ifidancitinib, a JAK inhibitor, reduced cisplatin-induced ototoxicity and improved hearing in mice.

Area of Science:

  • Ototoxicity research
  • Neuroscience
  • Pharmacology

Background:

  • Sensorineural hearing loss (SNHL) is a common disorder caused by irreversible damage to cochlear hair cells (HCs).
  • Cisplatin-induced ototoxicity is a significant clinical challenge, leading to hearing impairment.

Purpose of the Study:

  • To investigate the role of the JAK/STAT signaling pathway in cisplatin-induced ototoxicity.
  • To evaluate ifidancitinib, a JAK1/JAK3 inhibitor, as a potential therapeutic agent for preventing SNHL.

Main Methods:

  • Drug screening using the HEI-OC1 cell line.
  • Cochlear explant studies to assess protection against ototoxicity.
  • In vivo studies in adult mice using auditory brainstem response (ABR) and morphological analysis.
  • Western blot, MitoSOX Red assays, and ELISA to analyze molecular mechanisms.
  • STRING analysis and IL-2 inhibition/supplementation to elucidate the JAK-STAT5-IL2 axis.

Main Results:

  • Inhibition of the JAK/STAT pathway protected HEI-OC1 cells from cisplatin-induced ototoxicity.
  • Ifidancitinib demonstrated superior protection in cochlear explants and improved ABR thresholds and HC morphology in mice.
  • JAK/STAT signaling promoted ROS accumulation and apoptosis; ifidancitinib reduced proinflammatory markers.
  • The protective effects were mediated through the JAK/STAT5-IL2 axis.

Conclusions:

  • The JAK/STAT signaling pathway is crucial for hair cell survival and represents a viable therapeutic target for SNHL.
  • Ifidancitinib shows promise for preventing and treating sensorineural hearing loss caused by ototoxicity.
Keywords:
ApoptosisHearing lossIL-2Inflammatory reactionJAK inhibitors

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