{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T02:42:48Z","timestamp":1780972968418,"version":"3.54.1"},"reference-count":55,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T00:00:00Z","timestamp":1754352000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000646","name":"JSPS","doi-asserted-by":"publisher","award":["19K07687"],"award-info":[{"award-number":["19K07687"]}],"id":[{"id":"10.13039\/501100000646","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Chemotherapy remains a cornerstone in the treatment of esophageal cancer (EC), yet chemoresistance remains a critical challenge, leading to poor outcomes and limited therapeutic success. Mitochondrial DNA (mtDNA) has emerged as a pivotal player in mediating these responses, influencing cellular metabolism, oxidative stress regulation, and apoptotic pathways. This review provides a comprehensive overview of the mechanisms by which mtDNA alterations, including mutations and copy number variations, drive chemoresistance in EC. Specific focus is given to the role of mtDNA in metabolic reprogramming, including its contribution to the Warburg effect and lipid metabolism, as well as its impact on epithelial\u2013mesenchymal transition (EMT) and mitochondrial bioenergetics. Recent advances in targeting mitochondrial pathways through novel therapeutic agents, such as metformin and mitoquinone, and innovative approaches like CRISPR\/Cas9 gene editing, are also discussed. These interventions highlight the potential for overcoming chemoresistance and improving patient outcomes. By integrating mitochondrial diagnostics with personalized treatment strategies, we propose a roadmap for future research that bridges basic mitochondrial biology with translational applications in oncology. The insights offered in this review emphasize the critical need for continued exploration of mtDNA-targeted therapies to address the unmet needs in EC management and other diseases associated with mitochondria.<\/jats:p>","DOI":"10.3390\/biom15081128","type":"journal-article","created":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T10:50:21Z","timestamp":1754391021000},"page":"1128","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The Role of Mitochondrial DNA in Modulating Chemoresistance in Esophageal Cancer: Mechanistic Insights and Therapeutic Potential"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5178-9388","authenticated-orcid":false,"given":"Koji","family":"Tanaka","sequence":"first","affiliation":[{"name":"Departments of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasunori","family":"Masuike","sequence":"additional","affiliation":[{"name":"Department of Surgery, Osaka International Cancer Institute, Osaka 541-8567, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4017-1272","authenticated-orcid":false,"given":"Yuto","family":"Kubo","sequence":"additional","affiliation":[{"name":"Department of Esophageal Surgery, National Cancer Center Hospital East, Kashiwa 277-8577, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Harino","sequence":"additional","affiliation":[{"name":"Department of Surgery, Kansai Medical University, Hirakata 573-1191, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukinori","family":"Kurokawa","sequence":"additional","affiliation":[{"name":"Departments of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidetoshi","family":"Eguchi","sequence":"additional","affiliation":[{"name":"Departments of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichiro","family":"Doki","sequence":"additional","affiliation":[{"name":"Departments of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/S0140-6736(12)60643-6","article-title":"Oesophageal carcinoma","volume":"381","author":"Pennathur","year":"2013","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1510\/icvts.2009.222778","article-title":"Impact of number and site of lymph node invasion on survival of adenocarcinoma of esophagogastric junction","volume":"10","author":"Ielpo","year":"2010","journal-title":"Interact. 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