{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T08:03:50Z","timestamp":1789718630940,"version":"4.0.1"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T00:00:00Z","timestamp":1779062400000},"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. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The crotonylation reader DPF2 has been implicated in tumor progression, but its role in colon adenocarcinoma (COAD), especially in cell-type-specific immune regulation and metabolic reprogramming, remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted an integrative multi-omics study combining genetic association analysis for COAD, public transcriptomic validation data, CRC-context single-cell and spatial transcriptomic datasets used as supportive expression evidence, circulating metabolite profiling, and clinical immunohistochemistry. Two-sample Mendelian randomization was used to evaluate the association between genetically predicted expression of crotonylation-related genes and COAD risk, followed by validation and mechanistic analyses centered on DPF2.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Among 16 crotonylation-related candidate genes with available cis-eQTL evidence, only DPF2 showed a significant positive association with COAD risk. DPF2 was consistently upregulated in GEO datasets, TCGA-COAD, and clinical samples, and high DPF2 expression was associated with advanced disease and poor overall survival. Single-cell MR identified the strongest risk-associated signal in TCL1A\n                      <jats:sup>+<\/jats:sup>\n                      FCER2\n                      <jats:sup>+<\/jats:sup>\n                      B cells, with a suggestive association in CD8\n                      <jats:sup>+<\/jats:sup>\n                      S100B\n                      <jats:sup>+<\/jats:sup>\n                      T cells. Supportive analyses using public CRC-context single-cell and spatial transcriptomic datasets further indicated heterogeneous immune-cell expression and tumor-region enrichment of DPF2. In addition, DPF2 was significantly associated with 11 COAD-related circulating metabolites, and mediation analyses suggested partial mediation through Ximenoylcarnitine (C26:1), 16\u03b1-hydroxy DHEA 3-sulfate, and Andro steroid monosulfate C19H28O6S (1).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>DPF2 is a crotonylation reader associated with COAD risk and progression. Its effects may involve cell-type-specific immune regulation and partial mediation through metabolic reprogramming. While the primary causal inference of this study focused on COAD, complementary single-cell and spatial transcriptomic findings from broader CRC datasets provided supportive expression-level evidence consistent with these associations.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1835967","type":"journal-article","created":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T05:42:49Z","timestamp":1779082969000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The crotonylation reader DPF2 promotes the development and progression of colon adenocarcinoma through cell-type-specific immune regulation and metabolic reprogramming"],"prefix":"10.3389","volume":"17","author":[{"given":"Jingzhi","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Oncology, Zhongda Hospital, School of Medicine, Southeast University","place":["Nanjing, Jiangsu, China"]},{"name":"Department of Radiotherapy Oncology, The First People\u2019s Hospital of Yancheng, Yancheng No.1 People\u2019s Hospital, Affiliated Hospital of Medical School, Nanjing University","place":["Yancheng, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyi","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Oncology, Zhongda Hospital, School of Medicine, Southeast University","place":["Nanjing, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Oncology, Zhongda Hospital, School of Medicine, Southeast University","place":["Nanjing, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"809","DOI":"10.1016\/j.ccr.2014.04.026","article-title":"B cells regulate macrophage phenotype and response to chemotherapy in squamous carcinomas","volume":"25","author":"Affara","year":"2014","journal-title":"Cancer Cell"},{"key":"B2","doi-asserted-by":"publisher","first-page":"e00012","DOI":"10.1097\/in9.0000000000000012","article-title":"Steroid hormone regulation of immune responses in cancer","volume":"4","author":"Anderson","year":"2022","journal-title":"Immunometabolism (Cobham)"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/bs.vh.2024.10.002","article-title":"Targeting steroid hormone receptors for anti-cancer therapy","volume":"129","author":"Bhattacharyya","year":"2025","journal-title":"Vitam. 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