{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T06:50:58Z","timestamp":1791269458716,"version":"4.1.0"},"reference-count":50,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:00:00Z","timestamp":1791158400000},"content-version":"vor","delay-in-days":277,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Human Mutation"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Noise\u2010induced hearing loss (NIHL) is a key occupational hazard, and its specific pathogenic mechanism is not fully elucidated. Here, we performed this study to explore the potential role of single nucleotide polymorphisms (SNPs) located in the\n                      <jats:italic>PI3K\/AKT<\/jats:italic>\n                      pathway in human susceptibility to NIHL.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A case\u2010control study including 688 NIHL patients and 667 normal subjects was conducted. Genotype analysis was tested by multiplex polymerase chain reaction (PCR) with next generation sequencing. Luciferase assays were conducted to explore the effect of\n                      <jats:italic>SP1<\/jats:italic>\n                      on\n                      <jats:italic>PIK3R3<\/jats:italic>\n                      promoter activity. siRNA and cell transfection were used to determine the regulatory effect of\n                      <jats:italic>SP1\/PIK3R3<\/jats:italic>\n                      on HEI\u2010OC1 cells. qRT\u2010PCR and Western blotting were used to determine the expression of genes and proteins related to\n                      <jats:italic>PI3K\/AKT<\/jats:italic>\n                      , autophagy, and apoptosis. Cell counting kit 8 (CCK\u20108) assay was used to detect cell viability.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Subjects with\n                      <jats:italic>PIK3R3<\/jats:italic>\n                      rs7536272 GG genotype were more sensitive to NIHL than those with the AA\/AG genotypes and had a lower expression level of\n                      <jats:italic>PIK3R3<\/jats:italic>\n                      . Luciferase assay indicated that rs7536272 regulated\n                      <jats:italic>PIK3R3<\/jats:italic>\n                      expression by binding to\n                      <jats:italic>SP1<\/jats:italic>\n                      . Knockdown of\n                      <jats:italic>SP1<\/jats:italic>\n                      by siRNA and transfection into HEI\u2010OC1 cells inhibited the\n                      <jats:italic>PI3K\/AKT<\/jats:italic>\n                      pathway, indicated by the decreased phosphorylation levels of\n                      <jats:italic>PI3K<\/jats:italic>\n                      and\n                      <jats:italic>AKT<\/jats:italic>\n                      . Concurrently,\n                      <jats:italic>SP1<\/jats:italic>\n                      deficiency promoted autophagy, as evidenced by an elevated\n                      <jats:italic>LC3-II\/LC3-I<\/jats:italic>\n                      ratio and induced apoptosis, characterized by the reduction of\n                      <jats:italic>Bcl2<\/jats:italic>\n                      and the increase of\n                      <jats:italic>Bax<\/jats:italic>\n                      and\n                      <jats:italic>caspase-3<\/jats:italic>\n                      . Overexpression of\n                      <jats:italic>PIK3R3<\/jats:italic>\n                      partially restored the decreased activity of\n                      <jats:italic>PI3K\/AKT<\/jats:italic>\n                      pathway and attenuated the enhanced autophagy and apoptosis caused by\n                      <jats:italic>SP1<\/jats:italic>\n                      deficiency. CCK\u20108 assay revealed that\n                      <jats:italic>SP1<\/jats:italic>\n                      knockdown led to a time\u2010dependent decrease in cell viability, which was significantly rescued by the overexpression of\n                      <jats:italic>PIK3R3<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      All findings demonstrate that rs7536272 influences NIHL susceptibility by regulating\n                      <jats:italic>PIK3R3<\/jats:italic>\n                      expression in an allele\u2010specific manner by binding to\n                      <jats:italic>SP1<\/jats:italic>\n                      .\n                      <jats:italic>SP1<\/jats:italic>\n                      inhibits autophagy and apoptosis by activating\n                      <jats:italic>PIK3R3<\/jats:italic>\n                      \u2010mediated\n                      <jats:italic>PI3K\/AKT<\/jats:italic>\n                      pathway.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1155\/humu\/7010704","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T05:53:46Z","timestamp":1791266026000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Regulator SNP Affecting the Transcription Factor\n                    <i>SP1<\/i>\n                    Binding Site in the\n                    <i>PIK3R3<\/i>\n                    Gene Contributes to Noise\u2010Induced Hearing Loss Risk"],"prefix":"10.1155","volume":"2026","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6949-5855","authenticated-orcid":false,"given":"Long","family":"Miao","sequence":"first","affiliation":[{"name":"School of Nursing and School of Public Health 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yzu.edu.cn"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0297-5509","authenticated-orcid":false,"given":"Yu","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Radiology and Functional Examination Nanjing Prevention and Treatment Center for Occupational Diseases  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6519-7244","authenticated-orcid":false,"given":"Xiuli","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Nursing and School of Public Health Yangzhou University  Yangzhou China  yzu.edu.cn"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0650-7995","authenticated-orcid":false,"given":"Xiaoqin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Occupational Health Yangzhou Center for Disease Control and Prevention  Yangzhou 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