2. Academic Validation
  3. Pharmacological Inhibition of JAK/STAT-IL2 Axis Alleviated Cisplatin-Induced Ototoxicity

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

  • Mol Neurobiol. 2025 Nov 19;63(1):83. doi: 10.1007/s12035-025-05350-1.
Shimei Zheng # 1 2,  Chang Liu # 3,  Jiahuan Li # 1 2,  Hongbo Yu 4,  Siyu Qiu 1 2,  Wen Li 1 2,  Liping Zhao 1 2,  Xiangli Zeng 5,  Bing Chen 6 7,  Yingzi He 8 9
Affiliations

Affiliations

  • 1 ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, 83 Fenyang Road, Shanghai, 200031, China.
  • 2 NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai, 200031, China.
  • 3 Department of Otolaryngology-Head and Neck Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong, China.
  • 4 Shanghai Medical College, Fudan University, Shanghai, 200031, China.
  • 5 Department of Otolaryngology-Head and Neck Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong, China. [email protected].
  • 6 ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, 83 Fenyang Road, Shanghai, 200031, China. [email protected].
  • 7 NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai, 200031, China. [email protected].
  • 8 ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, 83 Fenyang Road, Shanghai, 200031, China. [email protected].
  • 9 NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai, 200031, China. [email protected].
  • # Contributed equally.
PMID: 41254428 DOI: 10.1007/s12035-025-05350-1
Abstract

Sensorineural hearing loss (SNHL) is recognized as one of the most common sensory disorders and is characterized by irreversible damage to cochlear hair cells (HCs). Our research, which utilized the HEI-OC1 cell line for drug screening, revealed that inhibiting the JAK/STAT signaling pathway protects HEI-OC1 cells from cisplatin-induced ototoxicity. Further studies with cochlear explants showed that ifidancitinib, an inhibitor of both JAK1 and JAK3, offered superior protection compared with Other JAK inhibitors. Additionally, in vivo studies with adult mice demonstrated that mice treated with ifidancitinib had lower auditory brainstem response (ABR) thresholds than those treated with cisplatin alone, along with improved morphology in HCs, nerve fibers, and pre- and postsynaptic structures. Western blot and MitoSOX Red assays demonstrated that the JAK/STAT signaling pathway promoted intracellular ROS accumulation and cell Apoptosis. Furthermore, ELISA showed that ifidancitinib significantly decreased the levels of proinflammatory markers such as TNF-α, CD38, IL-6, and IL-1β. STRING analysis revealed that ifidancitinib's protective effects on hearing were mediated through regulation of the JAK/STAT5-IL2 axis, which was further confirmed using an interleukin 2 (IL-2) inhibitor and animal-free IL-2 protein. This study underscores the importance of the JAK/STAT signaling pathway in HC survival, highlighting its potential as a therapeutic target for the prevention and treatment of SNHL.

Keywords

Apoptosis; Hearing loss; IL-2; Inflammatory reaction; JAK inhibitors.

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