TABLE 4.

Other novel mechanisms antagonizing cisplatin ototoxicity.

Classification	References	Agent	Mechanism
Combined drug administration	Curcio et al., 2022	LA@PCGC	LA@PCGC was injected in company with alginate-based hydrogel carrier guaranteeing an appropriate residence time for LA within the administration site.
	Febles et al., 2022	Combination of PFT-α, d-met, and NT3	The combination consisted of an antioxidant, neurotrophin and anti-apoptotic given prior to cisplatin exposure have significant cellular protective effect on cisplatin-induced death.
	Gu et al., 2022	ATX-PPS-NP	ATX-PPS-NP combines the effect of ROS consuming with the antioxidant effect and verifies a quick penetration across the round window membrane in guinea pigs.
	Valente et al., 2022	The conjugation of dexamethasone with nanoparticles	Another liquid crystalline nanoparticles combined with dexamethasone increases the drug diffusion and improves solubility and bioavailability of dexamethasone.
Regulating BLB permeability	Anfuso et al., 2022	Pericytes of Stria Vascularis	Cisplatin could induce the damage of bovine cochlear pericytes (BCPs) that regulate BLB permeability. Additional platelet-derived growth factor (PDGF-BB) induced a recovery of BCPs proliferation.
	Noman et al., 2022	Mannitol	Mannitol intravenous injections at t = 6 h reduced cisplatin ototoxicity through increasing the permeability of the blood labyrinth barrier (BLB).
Reducing cochlear metabolism	Stanford et al., 2021	Cool	Underlying mechanisms include blockage of upstream and downstream cell death pathways by reducing the uptake of cisplatin in cochlear cells, production of reactive oxygen species, and inflammation factor
	Tzelnick et al., 2022	Aspirin	Aspirin administration may could reduce cochlear metabolism and lead to reversible temporary threshold shift (TTS).
Affecting diverse cellular process	Lu et al., 2022a	Salubrinal	Both activating eukaryotic translation initiation factor2α (eIF2α) signaling pathway and its dephosphorylation inhibitor salubrinal significantly reduced endoplasmic reticulum and attenuated cell injury.
	Geohagen et al., 2023	Acetophenone	A novel acetophenone compounds can act as nucleophilic substitutes for cisplatin in platinum-cysteine thiolate site interactions which is responsible for cisplatin ototoxicity. And acetophenones have longer half-life period and can easily enter the cell.
	Yang et al., 2022	HSP70-BMSC-Exosomes	Overexpression of 70 kilodalton heat shock proteins (HSP70) in exosomes could alleviate cisplatin-induced hair cell loss mediated by NLRP3 inflammasome.
Trans-differentiation	Zhang et al., 2020	Foxg1	Foxg1 knockdown in supporting cells has been shown to lead to the generation of new hair cells.
	Zhang et al., 2023	Net1	Overexpression of the Guanine nucleotide exchange factor (Net1) induce supporting cell proliferation and hair cell regeneration.