Journal club: Role of GSDMD in facilitating the cell death pathway in cisplatin-induced sensorineural hearing loss model

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Today's journal article

Xiao Y, Zhang X, Guo S, Liu Z, Zhao X, Dong F, Bi X, Hong G, Chang M, Qiao R, Cao S, Liu Y, Xia M, Yuan W, Zhang J, Li W, Zhu L, Chai R, Gao J, Fu X. GSDMD-mediated mitochondrial dysfunction in marginal cells: A potential driver of inflammation and stria vascularis damage in CIHL. 

Why I picked this article

Cisplatin is a powerful chemotherapy for cancer. But a frequent side effect is the significantly increased risk of developing sensorineural hearing loss, the permanent form of hearing loss. This seems to be caused by the secondary effect of cisplatin- inflammation inside the inner ear seems to play a role, but the exact steps have not been clear.

The stria vascularis is the cochlea’s power plant. Cells in the stria vascularis pump potassium into the inner ear fluid called the endolymph to create the inner ear’s electrical “battery” (=the endocochlear potential). Cochlear hair cells use this battery to turn sound into nerve signals. Marginal cells are one type of cell found at the SV’s inner surface and do most of this ion pumping while not letting anything leak backwards by sealing the barrier with tight junctions. When marginal cells are injured, the loss of the barrier function and the battery leads to hearing loss. 

This research aims to understand how the inflammation caused by cisplatin may kill cells like marginal cells, by focusing on a protein called gasdermin D (GSDMD), and and whether blocking this pathway can protect the ear.

Some of the research findings

Animal model: 
  • C57BL/6N wild‑type mice (6–8 weeks old; both sexes)
  • Cisplatin-treatment: intraperitoneal 4mg/kg/day cisplatin in two cycles (4 consecutive daily injections, 3‑day break, then a second 4‑day cycle). 
  • Genetics: Gsdmd−/− mice were used to assess the requirement for GSDMD.
Pharmacological treatment: 
  • necrosulfonamide (GSDMD inhibitor) was given intraperitoneally as a pretreatment before each cisplatin dose.
  • disulfiram (an FDA‑approved pyroptosis inhibitor) was administered systemically during the cisplatin regimen. =>  both regimens reduced ABR threshold shifts and preserved SV structure in this model. 
Where the damage starts with cisplatin treatment: 
  • Cisplatin treatment: sensorineural hearing loss, accompanied by los off hair cells (particularly OHC), vascular degeneration in stria vascularis and increase in the inflammatory proteins (NLRP3, caspase and interleukins) were all confirmed. 
  • GSDMD protein was found in hair cells and cells of the stria vascularis in the cochlea. 
  • Gsdmd−/− mice showed markedly less cochlear injury with cisplatin treatment. 
  • Cisplatin treatment causes abnormal changes to the marginal cells of the cochlea. Microscopy images show mitochondria become more blobby. This again was mitigated in Gsdmd−/− mice. This suggests that GSDMD may have a role in the mitochondria. 
  • Using Hela cells (human cell line) and viral vectors, researchers overproduced activated GSDMD (GSDMD-N) or normal GSDMD. GSDMD-N was trapped in mitochondria, suggesting activated form of the protein indeed get trafficked to mitochondria. 
Overall, researchers suggest that in SV marginal cells, cisplatin triggers caspase‑dependent activation of GSDMD, which moves to mitochondria and activates the programmed cell death pathway.  
Part of Figure 5. Xiao et al. 2025 Diagram showing where GSDMD sits in the proposed pathway. 

Haruna's takeaway

This is a very comprehensive study focusing on the role of GSDMD protein function. I really enjoyed the focus and beautiful images of the marginal cells.  I do wonder how much of the activation of GSDMD is reversible, or if there is like a "critical level" of GSDMD activation beyond which there is a point of no return...? 

This research is also an reminder of how there is still a lot we don't know about the molecular pathways that eventually cause sensorineural hearing loss. 

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This is Haruna's 65/100 of the 100-day challenge to post a science blog article every day! I love inner ear biology & cochlear physiology.