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  3. 4-octyl itaconate alleviates cisplatin-induced ferroptosis possibly via activating the NRF2/HO-1 signalling pathway

4-octyl itaconate alleviates cisplatin-induced ferroptosis possibly via activating the NRF2/HO-1 signalling pathway

  • J Cell Mol Med. 2024 Apr;28(7):e18207. doi: 10.1111/jcmm.18207.
Li Zhang 1,  Wenao Song 2,  Hua Li 3,  Xiaolin Cui 2,  Jingyu Ma 1,  Rongrong Wang 2,  Yue Xu 2,  Ming Li 4,  Xiaohui Bai 1 2,  Dawei Wang 5,  Haihui Sun 6,  Zhiming Lu 1 2
Affiliations

Affiliations

  • 1 Department of Laboratory Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
  • 2 Department of Laboratory Medicine, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China.
  • 3 Department of Laboratory Medicine, Weishan County Second People's Hospital, Jining, Shandong, China.
  • 4 Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
  • 5 Department of Orthopaedics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
  • 6 Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
PMID: 38506087 DOI: 10.1111/jcmm.18207
Abstract

Ferroptosis, characterized by iron-dependent lipid Reactive Oxygen Species (ROS) accumulation, plays a pivotal role in cisplatin-induced ototoxicity. Existing research has suggested that in cisplatin-mediated damage to auditory cells and hearing loss, Ferroptosis is partially implicated. 4-Octyl itaconate (4-OI), derived from itaconic acid, effectively permeates cell membranes, showcasing potent anti-inflammatory as well as antioxidant effects in several disease models. Our study aimed to investigate the effect of 4-OI on cisplatin-induced Ferroptosis and the underlying molecular mechanisms. The survival rates of HEI-OC1 cells and mice cochlea hair cells were measured by CCK8 and immunofluorescence, respectively. The auditory brainstem response (ABR) audiometry was used to detect changes in hearing thresholds in mice before and after treatment. Levels of ROS were evaluated by DCFH-DA. Real-Time PCR quantified inflammatory cytokines TNF-α, IL-6 and IL-1β. Network Pharmacology and RNA Sequencing (RNA-seq) analysis of the potential mechanism of 4-OI resistance to cisplatin-induced Ferroptosis. The expressions of ferroptosis-related factors (GPX4, SLC7A11 and PTGS2) and important antioxidant factors (NRF2, HO-1, GCLC and NQO1) were tested by Real-Time PCR, Western blot and immunofluorescence. Results demonstrated cisplatin-induced significant ROS and inflammatory factor release, reduced NRF2 expression, hindered nuclear translocation and activated Ferroptosis. Pretreatment with 4-OI exhibited anti-inflammatory and antioxidant effects, along with resistance to Ferroptosis, ultimately mitigating cisplatin-induced cell loss. In the present study, we show that 4-OI inhibits cisplatin-induced Ferroptosis possibly through activation of the NRF2/HO-1 signalling pathway, thereby exerting a protective effect against cisplatin-induced damage to auditory cells, and providing a new therapeutic strategy for cisplatin-induced hearing loss.

Keywords

4-octyl itaconate; NRF2; cisplatin; ferroptosis; ototoxicity.

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