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Whether distinct underlying mechanisms can further classify PTC and improve prognostic precision remains unclear.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>We integrated single-cell RNA sequencing data (158,577 cells from 11 PTC patients; GEO: GSE184362) with bulk-RNA sequencing data from The Cancer Genome Atlas Thyroid Carcinoma (TCGA-THCA) cohort (501 patients). Multi-omics analyses were employed to elucidate PTC heterogeneity, identify malignant cell differentiation and prognosis-related genes (MCD&amp;PRGs), and construct a novel molecular classification, the Oncogenic Signature Of Papillary Thyroid Carcinoma Classification (OSPTCC). A prognostic risk score was developed, and the classification's prognostic relevance was further explored in an independent institutional cohort using qRT-PCR.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Single-cell analysis revealed three malignant cell differentiation states (PTC1-3) and a 34-gene signature (MCD&amp;PRGs). This formed the basis of our Oncogenic Signature Of Papillary Thyroid Carcinoma Classification (OSPTCC), defining three subtypes: Inflammation-associated (IPTCC), BRAF\/autophagy-related (BAPTCC), and lipid metabolism-related (LPTCC). These subtypes showed distinct molecular profiles and significantly different progression-free survival (IPTCC poorest, <jats:italic>P<\/jats:italic>\u2009=\u20090.044). A 7-gene risk score derived from MCD&amp;PRGs independently predicted prognosis (multivariate <jats:italic>HR<\/jats:italic>\u2009=\u200921.511, <jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001). qRT-PCR validation in an independent cohort (n\u2009=\u200948) using key markers (DEPTOR, APOE, APOC1) confirmed that OSPTCC-based risk stratification correlated with adverse clinical features, including higher recurrence rates in the high-risk group (<jats:italic>P<\/jats:italic>\u2009=\u20090.007).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>This study introduces OSPTCC, a prognostically significant molecular classification for PTC based on tumor cell differentiation states. The identified subtypes, characterized by distinct biological mechanisms, provide deeper insights into PTC's molecular pathology and offer a framework for improved risk stratification and potential precision therapies.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1007\/s00262-025-04101-4","type":"journal-article","created":{"date-parts":[[2025,7,12]],"date-time":"2025-07-12T10:31:49Z","timestamp":1752316309000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Single-cell RNA sequencing and multi-omics analysis of prognosis-related staging in papillary thyroid cancer"],"prefix":"10.1007","volume":"74","author":[{"given":"Guo","family":"Ji","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanlin","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simo","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuechen","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Le","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruting","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2302-7305","authenticated-orcid":false,"given":"Runzhi","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijun","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengyan","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,12]]},"reference":[{"issue":"11","key":"4101_CR1","doi-asserted-by":"publisher","first-page":"1054","DOI":"10.1056\/NEJMra1501993","volume":"375","author":"JA Fagin","year":"2016","unstructured":"Fagin JA, Wells SA Jr (2016) Biologic and Clinical Perspectives on Thyroid Cancer. 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