{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T06:05:14Z","timestamp":1780553114903,"version":"3.54.1"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T00:00:00Z","timestamp":1780531200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>While papillary thyroid carcinoma (PTC) generally exhibits a favorable prognosis, a subset of patients experiences poorer outcomes, with lymph node metastasis (LNM) significantly increasing the risk of recurrence and correlating with a worse prognosis. Mitochondrial metabolic reprogramming and immune evasion play pivotal roles in driving lymph node metastasis; however, the specific actionable targets within these processes remain largely unexplored.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We constructed a multi-omics discovery framework by integrating TCGA\/GTEx transcriptomics, a large-scale independent clinical cohort, and single-cell RNA sequencing. Both mitochondrial metabolic signatures and immune evasion landscapes were investigated to characterize their roles in driving LNM. A consensus machine learning framework was deployed to isolate core drivers, which were rigorously validated through genetic manipulation and pharmacological assays.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Unsupervised clustering identified a high-risk \u201cMito-high\u201d subtype, characterized by distinct metabolic reprogramming and an immunosuppressive microenvironment, in which CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell depletion coincided with Treg enrichment. Machine learning prioritized MGST1 as the core predictor, consistently ranking as a top feature in both the integrated TCGA\/GTEx dataset and our independent cohort. The MGST1-based model demonstrated robust predictive performance, achieving an AUC of 0.833 in external validation. At the single-cell level, trajectory analysis positioned MGST1 at the terminal stage of dedifferentiation, marking a stem-like metastatic subpopulation. Pharmacological inhibition of MGST1 with Toxoflavin dose-dependently suppressed proliferation, migration, and invasion while inducing apoptosis. Critically, pharmacological inhibition of MGST1 may reverse the \u201cimmune-cold\u201d phenotype by promoting IL-1\u03b2 release and suppressing TGF-\u03b21. siRNA-mediated knockdown confirmed the target dependency of Toxoflavin.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings uncover a previously unrecognized link between mitochondrial metabolic reprogramming, immune evasion and LNM in PTC and establish MGST1 as a robust biomarker for metastatic risk stratification and a pivotal metabolic-immune regulator. Moreover, the target-specific activity of toxoflavin provides a rational therapeutic strategy for patients with high-risk PTC characterized by MGST1-driven mitochondrial reprogramming and immune evasion.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1848083","type":"journal-article","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T05:43:23Z","timestamp":1780551803000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["MGST1 drives lymph node metastasis in papillary thyroid carcinoma via mitochondrial metabolic reprogramming and immune suppression"],"prefix":"10.3389","volume":"17","author":[{"given":"Qing-Xuan","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Thyroid Surgery, The First Affiliated Hospital of Wenzhou Medical University","place":["Wenzhou, Zhejiang, China"]},{"name":"Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, First Affiliated Hospital, Wenzhou Medical University","place":["Wenzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang-Feng","family":"Yu","sequence":"additional","affiliation":[{"name":"School of Ophthalmology & Optometry, Wenzhou Medical University","place":["Wenzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke-Chen","family":"Zhang","sequence":"additional","affiliation":[{"name":"The First Clinical Medical College, Wenzhou Medical University","place":["Wenzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun-Hao","family":"Zhang","sequence":"additional","affiliation":[{"name":"The First Clinical Medical College, Wenzhou Medical University","place":["Wenzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu-Jie","family":"Zhou","sequence":"additional","affiliation":[{"name":"The First Clinical Medical College, Wenzhou Medical 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China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai-Bo","family":"Su","sequence":"additional","affiliation":[{"name":"The First Clinical Medical College, Wenzhou Medical University","place":["Wenzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"You","sequence":"additional","affiliation":[{"name":"Department of Thyroid Surgery, The First Affiliated Hospital of Wenzhou Medical University","place":["Wenzhou, Zhejiang, China"]},{"name":"Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, First Affiliated Hospital, Wenzhou Medical University","place":["Wenzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-Miao","family":"Qu","sequence":"additional","affiliation":[{"name":"Department of Thyroid Surgery, The First Affiliated Hospital of Wenzhou Medical University","place":["Wenzhou, Zhejiang, China"]},{"name":"Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, First Affiliated Hospital, Wenzhou Medical University","place":["Wenzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cong","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Zhejiang Dinghai Hospital, Shanghai Ruijin Hospital Zhoushan Branch","place":["Zhoushan, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University","place":["Wenzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye-Feng","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Thyroid Surgery, The First Affiliated Hospital of Wenzhou Medical University","place":["Wenzhou, Zhejiang, China"]},{"name":"Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and 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