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However, the direct mechanisms through which hypoxia\u2010induced ROS are sensed and contribute to therapeutic resistance remain elusive. ROS can regulate the function of transcription factors through oxidation of cysteine thiol groups, but the compartmentalization limits their physical interaction with transcription factors. Here, BHLHE40, a transcription factor traditionally recognized for its nuclear function, is identified as a novel mitochondrial sensor of hypoxia\u2010induced ROS. Mitochondrial BHLHE40 experiences ROS\u2010dependent oxidation of cysteine thiol groups and forms disulfide\u2010linked homodimers. In addition to post\u2010translational modification that regulates BHLHE40 protein levels, hypoxia also increases BHLHE40 mRNA levels through hypoxia\u2010inducible factors (HIFs)\u2010dependent transcriptional activation. These dual mechanisms of modulating BHLHE40 ensure its rapid elevation during the early stage of hypoxia. Functionally, BHLHE40 plays a critical role in hypoxia\u2010induced radioresistance through transcriptional activation of cellular antioxidant systems and inhibition of cytotoxic effects mediated by irradiation\u2010generated ROS. This study reveals a previously unrecognized role of BHLHE40 in sensing and regulating ROS in response to hypoxia, and highlights its potential as a therapeutic target to overcome hypoxia\u2010promoted radioresistance in TNBC.<\/jats:p>","DOI":"10.1002\/advs.76864","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T12:54:31Z","timestamp":1785156871000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Intratumoral Hypoxia Triggers Mitochondrial BHLHE40 ROS Sensing Pathway to Promote Radioresistance in Triple\u2010Negative Breast Cancer"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2670-5389","authenticated-orcid":false,"given":"Jia","family":"Liu","sequence":"first","affiliation":[{"name":"Advanced Medical Research Institute Cheeloo College of Medicine Shandong University  Jinan Shandong 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