{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,16]],"date-time":"2026-08-16T04:26:57Z","timestamp":1786854417858,"version":"build-2736575974"},"reference-count":41,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"State Key Laboratory of Trauma and Chemical Poisoning","award":["SKLO202509"],"award-info":[{"award-number":["SKLO202509"]}]},{"DOI":"10.13039\/501100004608","name":"Natural Science Foundation of Jiangsu Province","doi-asserted-by":"crossref","award":["BK20230742"],"award-info":[{"award-number":["BK20230742"]}],"id":[{"id":"10.13039\/501100004608","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Joint Open Research Fund of State Key Laboratory of Digital Medical Engineering and Organ-on-Chip Commercialization Platform","award":["DIGIMED20260209"],"award-info":[{"award-number":["DIGIMED20260209"]}]},{"name":"Technical Project of Jiangsu Provincial Occupational Health Research Program","award":["JSZJ20241101"],"award-info":[{"award-number":["JSZJ20241101"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Noise-induced hearing loss (NIHL) is a pervasive occupational health challenge, yet the individual susceptibility mechanisms remain unclear. Ferroptosis, an iron-dependent form of programmed cell death, has been implicated in cochlear hair cell damage. This study aims to elucidate the regulatory role of the transcription factor FOXA2 and the deacetylase SIRT1 in ferroptosis and to investigate the association between SIRT1 genetic polymorphisms and NIHL susceptibility in occupational populations. Methods: We employed a multi-level study design combining epidemiological investigation, animal models, and cellular experiments. First, a case\u2013control study was conducted involving 1314 noise-exposed workers (639 cases vs. 675 controls) from a chemical fiber enterprise in Jiangsu Province to analyze the association between SIRT1 single nucleotide polymorphisms (SNPs) and NIHL risk. Second, a C57BL\/6J mouse model exposed to 120 dB white noise was established to assess cochlear morphology and protein expression. Third, in HEI-OC1 cochlear hair cells, we performed siRNA-mediated knockdown of Foxa2 and dual-luciferase reporter assays to verify the transcriptional regulation of SIRT1 and its downstream effects on the ferroptosis pathway. Results: Population analysis revealed that the SIRT1 rs12778366 C allele was significantly associated with increased NIHL risk (OR = 1.386, 95% CI: 1.084\u20131.772, p = 0.009), and this association remained significant after adjustment (p = 0.041). Stratified analysis further revealed a significant gene\u2013environment interaction in workers with &gt;15 years of noise exposure (OR = 2.126, 95% CI: 1.401\u20133.226, p &lt; 0.001). In vivo, noise exposure led to significant downregulation of Sirt1 and Foxa2 in cochlear tissues, accompanied by elevated ferroptosis markers (Fe2+, MDA) and depleted antioxidant defenses (GSH, xCT, and GPX4). Mechanistically, we demonstrate that FOXA2 transcriptionally activates SIRT1 by binding to its promoter. Knockdown of FOXA2 in vitro suppressed SIRT1 expression, suppressed xCT, a key component of the System Xc\u2212\/GPX4 antioxidant axis, and promoted ferroptosis-related cellular changes. Conclusions: This study identifies a novel protective axis where FOXA2 prevents noise-induced ferroptosis in cochlear hair cells by transcriptionally upregulating SIRT1 and maintaining xCT-mediated antioxidant defense. Furthermore, the SIRT1 rs12778366 polymorphism is identified as a candidate variant warranting further investigation in independent cohorts before clinical translation.<\/jats:p>","DOI":"10.3390\/genes17080953","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T09:04:01Z","timestamp":1786698241000},"page":"953","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["FOXA2 Transcriptionally Activates SIRT1 to Inhibit Cochlear Ferroptosis in Noise-Induced Hearing Loss"],"prefix":"10.3390","volume":"17","author":[{"given":"Xiaoru","family":"Dai","sequence":"first","affiliation":[{"name":"School of Public Health, Nanjing Medical University, Nanjing 211166, China"},{"name":"Institute of Occupational Disease Prevention, Jiangsu Provincial Center for Disease Control and Prevention, No. 172 Jiangsu Road, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Sun","sequence":"additional","affiliation":[{"name":"Liyang Centre for Disease Control and Prevention, Changzhou 213300, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minyun","family":"Jiang","sequence":"additional","affiliation":[{"name":"Jiading District Center for Patriotic Health and Health Promotion Guidance, Shanghai 201800, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lizhuang","family":"Xie","sequence":"additional","affiliation":[{"name":"Institute of Occupational Disease Prevention, Jiangsu Provincial Center for Disease Control and Prevention, No. 172 Jiangsu Road, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hengdong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Occupational Disease Prevention, Jiangsu Provincial Center for Disease Control and Prevention, No. 172 Jiangsu Road, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baoli","family":"Zhu","sequence":"additional","affiliation":[{"name":"School of Public Health, Nanjing Medical University, Nanjing 211166, China"},{"name":"Institute of Occupational Disease Prevention, Jiangsu Provincial Center for Disease Control and Prevention, No. 172 Jiangsu Road, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boshen","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Occupational Disease Prevention, Jiangsu Provincial Center for Disease Control and Prevention, No. 172 Jiangsu Road, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"525","DOI":"10.12968\/hmed.2019.80.9.525","article-title":"What Is Noise-Induced Hearing Loss?","volume":"80","author":"Ding","year":"2019","journal-title":"Br. 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