Although cisplatin is a widely used chemotherapeutic agent, it is severely toxic and causes irreversible hearing loss, restricting its application in clinical settings. This study aimed to determine the molecular mechanism underlying cisplatin-induced ototoxicity. Here, we established in vitro and in vivo ototoxicity models of cisplatin-induced hair cell loss, and our results showed that reducing STING levels decreased inflammatory factor expression and hair cell death. In addition, we found that cisplatin-induced mitochondrial dysfunction was accompanied by cytosolic DNA, which may act as a critical linker between the cyclic GMP-AMP synthesis-stimulator of interferon genes (cGAS-STING) pathway and the pathogenesis of cisplatin-induced hearing loss. H-151, a specific inhibitor of STING, reduced hair cell damage and ameliorated the hearing loss caused by cisplatin in vivo. This study underscores the role of cGAS-STING in cisplatin ototoxicity and presents H-151 as a promising therapeutic for hearing loss.
Cisplatin/toxicity* ; Animals ; Nucleotidyltransferases/antagonists & inhibitors* ; Membrane Proteins/antagonists & inhibitors* ; Signal Transduction/drug effects* ; Mice ; Hair Cells, Auditory, Inner/pathology* ; Antineoplastic Agents/toxicity* ; Mice, Inbred C57BL ; Hearing Loss/metabolism* ; Male ; Ototoxicity/metabolism*

BACKGROUND: Endoscopic biopsy can underestimate gastric malignancies as low-grade intraepithelial neoplasia (LGIN). Definitively diagnosed LGIN would progress. This study aimed to evaluate predictive factors to identify malignancies misdiagnosed as LGIN by biopsy and LGIN at high risk of progression. METHODS: The clinical records of patients diagnosed with gastric LGIN by endoscopic biopsy who underwent at least two endoscopies during the first year of follow-up between 2007 and 2017 were retrospectively collected. Three endoscopists reviewed photographs of the initial endoscopy, described lesion characteristics, and made endoscopic diagnoses. Logistic regression was used to analyze predictors to identify malignancies underestimated as LGIN. A receiver operating characteristic curve was used to evaluate the diagnostic accuracy of these predictors. Patient clinical outcomes of follow-up >1 year were collected. Kaplan-Meier estimates with log-rank tests and Cox proportional hazards regression were used to analyze predictors of progression. RESULTS: Overall, 48 of 182 (26.4%) patients were proven to have malignancies. A single lesion, a large lesion size, and marked intestinal metaplasia (IM) were independent predictors of initially misdiagnosed malignancies. The area under the curve of these predictors was 0.871, with a sensitivity of 68.7% and specificity of 92.5%. Twelve of 98 patients (12.2%) progressed during the 33-month median follow-up period. A whitish appearance, irregular margins, marked IM, and histological diagnosis of LGIN more than twice within the first year were predictors for progression. CONCLUSIONS Lesions diagnosed as LGIN by biopsy with marked IM and other predictors above should be prudently treated for high potential to be malignancies or progress. Endoscopic follow-up with repeated biopsies within the first year is recommended.
Biopsy ; Carcinoma in Situ ; Endoscopy ; Humans ; Prognosis ; Retrospective Studies ; Stomach Neoplasms/diagnosis*