{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T01:24:05Z","timestamp":1781659445050,"version":"3.54.5"},"reference-count":69,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T00:00:00Z","timestamp":1768348800000},"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>Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy, with rising incidence worldwide. Oxidative stress (OS), characterized by an imbalance between reactive oxygen species (ROS) and antioxidant defenses, plays a critical role in tumor initiation and progression. However, the specific relationship between OS and PTC remains underexplored, highlighting the need for further investigation. This study aims to identify OS-related biomarkers in PTC that could potentially be used for clinical diagnosis and treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Single-cell RNA sequencing data from PTC and normal thyroid tissues were analyzed using multiple gene set scoring and differential expression methods to evaluate OS levels across different cell types. Integrated bioinformatics analysis, including WGCNA and machine learning models, was employed to select candidate biomarkers, which were then validated in independent datasets. Pseudotime analysis and CellChat were conducted to explore cell dynamics within the tumor microenvironment. An oxidative stress model was established in TPC-1 cells using hydrogen peroxide treatment. The levels of OS and changes in tumor cell proliferative capacity were assessed through western blotting, immunoblotting, ROS detection, and cell viability assays.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The study revealed that\n                      <jats:italic>CCND1<\/jats:italic>\n                      and\n                      <jats:italic>SOX4<\/jats:italic>\n                      were highly expressed in PTC, promoting tumor cell proliferation, invasion, and maintaining an undifferentiated state. Both genes were closely linked to OS, which amplified their expression and enhanced tumor growth and immune evasion.\n                      <jats:italic>CCND1<\/jats:italic>\n                      was particularly involved in M2 macrophage polarization via the PROS1-AXL pathway, while\n                      <jats:italic>SOX4<\/jats:italic>\n                      regulated angiogenesis through the MDK pathway. In contrast,\n                      <jats:italic>TFF3<\/jats:italic>\n                      expression was significantly lower in PTC, suggesting a tumor-suppressive role, potentially through modulating immune responses and reducing OS.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      <jats:italic>CCND1<\/jats:italic>\n                      is identified as a key oncogene in PTC, whose high expression promotes tumor progression through OS-related pathways like PI3K\/AKT and MAPK. Our\n                      <jats:italic>in vitro<\/jats:italic>\n                      findings specifically validate that OS directly drives\n                      <jats:italic>CCND1<\/jats:italic>\n                      overexpression and subsequent cell proliferation. Conversely,\n                      <jats:italic>SOX4<\/jats:italic>\n                      also acts as an oncogene, and\n                      <jats:italic>TFF3<\/jats:italic>\n                      as a potential tumor suppressor, both linked to OS. Targeting\n                      <jats:italic>CCND1<\/jats:italic>\n                      and its OS-mediated regulatory pathways offers a promising therapeutic strategy for PTC.\n                    <\/jats:p>\n                    <jats:p>\n                      <jats:italic>CCND1<\/jats:italic>\n                      , oxidative stress, papillary thyroid carcinoma, single-cell RNA sequencing,\n                      <jats:italic>SOX4<\/jats:italic>\n                      ,\n                      <jats:italic>TFF3<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1722524","type":"journal-article","created":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T06:41:22Z","timestamp":1768372882000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Single-cell and machine learning integration reveals OS-driven CCND1 promotes an aggressive 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China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanqing","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Thyroid Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"17","DOI":"10.3322\/caac.21763","article-title":"Cancer statistics, 2023","volume":"73","author":"Siegel","year":"2023","journal-title":"CA Cancer J Clin"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2017.2719","article-title":"Trends in thyroid cancer incidence and mortality 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