{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T17:56:57Z","timestamp":1790618217650,"version":"4.1.0"},"reference-count":25,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":21,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Reports"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>N4\u2010acetylcytidine (ac4C) RNA modification has emerged as a critical epigenetic regulator in tumorigenesis and progression. However, the comprehensive landscape of ac4C modification in colorectal cancer (CRC), particularly its orchestration of the tumor microenvironment (TME) and stromal crosstalk, remains largely unexplored.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>This study aimed to comprehensively delineate the landscape of N4\u2010acetylcytidine (ac4C) RNA modification in colorectal cancer (CRC) to uncover its role in shaping the tumor microenvironment and clinical outcomes. Integrated bioinformatic and in\u00a0vitro analyses revealed that ac4C patterns dictate aggressive stromal crosstalk and identified CERCAM as a cancer\u2010associated fibroblast (CAF)\u2010specific driver of tumor progression, providing a novel framework for prognostic prediction and personalized targeted therapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Transcriptomic and clinical data of CRC patients were curated from TCGA and GEO databases (GSE14333, GSE17536, GSE38832, GSE39582). The ac4C modification patterns were quantified using single\u2010sample Gene Set Enrichment Analysis (ssGSEA). Single\u2010cell RNA sequencing (scRNA\u2010seq) analyses were performed via the scCancer Explorer database. A prognostic ac4C score was constructed to evaluate clinical outcomes and therapeutic vulnerabilities. The functional role of the identified target gene, CERCAM, was validated using in\u00a0vitro co\u2010culture experiments.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Patients with high ac4C scores exhibited worse prognosis, higher clinical stages, and metastasis (N2, M1). High ac4C levels positively correlated with epithelial\u2010mesenchymal transition (EMT), TGF\u2010\u03b2 signaling, and extracellular matrix (ECM) receptor interactions, whereas low ac4C levels were associated with cell cycle, fatty acid metabolism, and microsatellite stability (MSS). The TME of high\u2010ac4C tumors was characterized by higher Stromal, Immune, and ESTIMATE scores, elevated immune checkpoints (LAG3, CD14, LILRB2, SIRPA, CD8A), and strong correlations with macrophages and NK cells. scRNA\u2010seq analysis revealed that CERCAM, a key gene within the ac4C network, was predominantly expressed in cancer\u2010associated fibroblasts (CAFs) rather than tumor cells. DNA methylation of CERCAM was significantly elevated in metastatic CRC compared to primary tumors. In\u00a0vitro experiments confirmed that CERCAM was overexpressed in CAFs and CRC tissues. Co\u2010culturing CRC cells (RKO, HCT116) with CERCAM\u2010knockdown CAFs significantly suppressed tumor cell proliferation, migration, and invasion. Furthermore, the ac4C score effectively predicted tumor mutational landscape differences and sensitivities to agents like pazopanib, gefitinib, and conventional chemotherapies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study delineates the crucial role of ac4C modification in shaping the CRC microenvironment, identifies CERCAM as a CAF\u2010specific driver of tumor progression, and provides a translational framework for ac4C\u2010based prognostic prediction and personalized targeted therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cnr2.70677","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T05:36:04Z","timestamp":1790141764000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Comprehensive Profiling of\n                    <scp>ac4C RNA<\/scp>\n                    Modification Identifies\n                    <scp>CERCAM<\/scp>\n                    in Cancer\u2010Associated Fibroblasts as a Key Prognostic and Microenvironmental Regulator in Colorectal Cancer"],"prefix":"10.1002","volume":"9","author":[{"given":"Yang","family":"Xia","sequence":"first","affiliation":[{"name":"Department of General Surgery The Affiliated Hospital With Jiangnan University  Wuxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jialin","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Kunshan Hospital of Tranditional Chinese Medicine  Suzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2150-3414","authenticated-orcid":false,"given":"Xinyi","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of General Surgery The Affiliated Hospital With Jiangnan University  Wuxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruige","family":"Zhang","sequence":"additional","affiliation":[{"name":"Ansteel General Hospital  Anshan China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,22]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2021.0106"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-15-2879"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-022-02551-7"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.2174\/0109298665256238231120093150"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.2174\/0109298665305114240718072029"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.2174\/0109298665297110240611115010"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.10.030"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-025-02100-2"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-025-08315-3"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2025.139823"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-019-0115-0"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.08.003"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbaa127"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-23-1418"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41421-025-00781-5"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-025-07656-3"},{"key":"e_1_2_13_19_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1195300"},{"key":"e_1_2_13_20_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12903-023-03421-0"},{"key":"e_1_2_13_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-019-0238-1"},{"key":"e_1_2_13_22_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00048.2019"},{"key":"e_1_2_13_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2017.12.004"},{"key":"e_1_2_13_24_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a026781"},{"key":"e_1_2_13_25_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-08-2740"},{"key":"e_1_2_13_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-018-0007-6"}],"container-title":["Cancer 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