TABLE 3.

Inhibitors of cellular pathway antagonizing cisplatin ototoxicity.

Cellular pathway	References	Agent	Mechanism
Apoptosis	Borse et al., 2017	Epigallocatechin-3-gallate	Epigallocatechin-3-gallate inhibits the signal transducer and activator of transcription1 (STAT1) expression, thereby reducing UB/CO1 cell apoptosis induced by caspase-3 and Bax.
	Zhang et al., 2022a	Agmatine	Agmatine upregulate PI3K/AKT pathway to alleviate cisplatin-induced cochleae cell apoptosis.
	Liu et al., 2022	CPI-455	KDM5A regulates H3K4me3 demethylation, and its inhibitor CPI-455 regulate MAPK and PI3K/AKT signaling to attenuate cisplatin-induced ototoxicity.
	Zheng et al., 2022	Rutin	Rutin could suppress MAPK/JNK signaling and activate PI3K/AKT signaling reducing mitochondria and auditory neural damage after cisplatin exposure.
Mitochondrial apoptosis.	Lu et al., 2022b	Eupatilin	Eupatilin intervenes mitochondrial apoptosis pathway in vitro and in vivo models.
	He et al., 2022b	RG108	RG108 protects mitochondrial function through preventing ROS accumulation induced mitochondrial apoptosis.
	Xu et al., 2022	Puerarin	Puerarin, a traditional Chinese medicine extract, also can inhibit ROS overproduction, regulate Bcl-2 family and AKT level to regulate mitochondrial apoptosis pathway.
Autophagy	Li et al., 2018	Meclofenamic Acid	Meclofenamic acid reduces ROS accumulation and apoptosis and improves hair cell-like HEI-OC1 cell viability by inhibiting cisplatin-induced excessive autophagy.
	Li et al., 2022e	Trehalose	Trehalose protects against cisplatin-induced cochlear hair cell damage by autophagy attributed to increasing nuclear translocation of transcription factor EB (TFEB).
	Huang et al., 2022	YTHDF1	YTHDF1 can regulate RNA metabolism through binding to specific m6A motifs and promote autophagy via increased AG14 translation among HEI-OC1 cells.
	Liu et al., 2021a	PRDX1	Modulating the activation of the antioxidant enzyme peroxiredoxin 1 (PRDX1) can have an impact on both ROS accumulation and autophagy.
Apoptosis and autophagy	Wang et al., 2021	U0126	U0126, a specific inhibitor of the extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) signaling pathway, has neuroprotective effects.
Nrf2 signaling pathway	Wang et al., 2022	Nrf2	Nrf2 knockout inhibits ferroptosis through increasing GPX4 protein levels and decreasing TfR1 protein levels.
	Li et al., 2022a	Polydatin	Polydatin can ameliorate oxidative stress and apoptosis injury through activating the Nrf2/HO-1 signaling pathway.
	Adachi et al., 2023	Estradiol	Estradiol activated the Nrf2 signaling pathway and the transcription of genes encoding phase II detoxification enzymes.
JNK/FoxO1 signaling pathway	Li et al., 2023	D4M	5,7-Dihydroxy-4-methylcoumarin (D4M)markedly regulated p-JNK and elevated the expression ratio of p-FoxO1/FoxO1.
LMO4 signaling pathway	Fritzsche et al., 2022	Nimodipine	Nimodipine pre-treatment regulates LMO4 levels and activates of associated Akt, CREB and Stat3 protein levels.