{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T04:13:29Z","timestamp":1793420009985,"version":"4.5.0"},"reference-count":31,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T00:00:00Z","timestamp":1782086400000},"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. Genet."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Hepatocellular carcinoma (HCC) is characterized by extensive epigenetic alterations, particularly DNA methylation. Through integrated multi-omics analysis, we identified methylation-driven genes in HCC, including PHYHD1\u2014a previously understudied candidate whose role in hepatocarcinogenesis remains unexplored. This study aimed to validate and functionally characterize PHYHD1 in HCC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Five pairs of HCC and adjacent non-tumor tissues were analyzed using whole-genome bisulfite sequencing (WGBS), RNA-seq, and TMT-based proteomics. We identified 97,523 differentially methylated regions (DMRs), 875 differentially expressed genes (DEGs), and 225 differentially expressed proteins (DEPs).\n                      <jats:italic>PHYHD1<\/jats:italic>\n                      hypermethylation was confirmed by public methylation datasets, and its mRNA\/protein expression was validated by RT-qPCR, Western blot, and immunohistochemistry in cell lines, patient tissues (n = 76 pairs), and a DEN\/CCl\n                      <jats:sub>4<\/jats:sub>\n                      -induced murine HCC model. Functional effects were assessed via\n                      <jats:italic>in vitro<\/jats:italic>\n                      assays (CCK-8, colony formation, flow cytometry) and an\n                      <jats:italic>in vivo Phyhd1<\/jats:italic>\n                      knockout model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Integration of methylome, transcriptome, and proteome data revealed 19 consistently altered genes enriched in metabolic pathways.\n                      <jats:italic>PHYHD1<\/jats:italic>\n                      was hypermethylated and downregulated at both mRNA and protein levels in HCC. However, gain- or loss-of-function of PHYHD1 had no detectable effect on proliferation, apoptosis, or tumorigenicity\n                      <jats:italic>in vitro<\/jats:italic>\n                      or\n                      <jats:italic>in vivo<\/jats:italic>\n                      (all\n                      <jats:italic>P<\/jats:italic>\n                      &amp;gt; 0.05).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      Integrated multi-omics analysis identified\n                      <jats:italic>PHYHD1<\/jats:italic>\n                      as an epigenetically silenced gene in HCC, but functional studies indicate that its silencing does not act as a canonical driver of malignant phenotypes. Instead,\n                      <jats:italic>PHYHD1<\/jats:italic>\n                      hypermethylation may represent a passenger event or a context-dependent modulator that only exerts effects under specific stress conditions (e.g., hypoxia or metabolic inflammation). These findings suggest that not all methylation-driven genes in HCC are functional drivers, and they highlight the need for further investigation into passenger epigenetic alterations in tumor biology.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fgene.2026.1848528","type":"journal-article","created":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T04:38:14Z","timestamp":1782103094000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Epigenetic silencing of PHYHD1 in hepatocellular carcinoma revealed by integrated multi-omics analysis"],"prefix":"10.3389","volume":"17","author":[{"given":"Tianfu","family":"Guo","sequence":"first","affiliation":[{"name":"Key Laboratory of Innate Immunity and Chronic Inflammatory Diseases, Jiangxi Provincial Department of Education, Gannan Medical University","place":["Ganzhou, China"]},{"name":"Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University","place":["Ganzhou, China"]},{"name":"School of Basic Medicine, Gannan Medical University","place":["Ganzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yafei","family":"Li","sequence":"additional","affiliation":[{"name":"School of Basic Medicine, Gannan Medical University","place":["Ganzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiansheng","family":"He","sequence":"additional","affiliation":[{"name":"Key Laboratory of Innate Immunity and Chronic Inflammatory Diseases, Jiangxi Provincial Department of Education, Gannan Medical University","place":["Ganzhou, China"]},{"name":"Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University","place":["Ganzhou, China"]},{"name":"School of Basic Medicine, Gannan Medical University","place":["Ganzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Luo","sequence":"additional","affiliation":[{"name":"School of Basic Medicine, Gannan Medical University","place":["Ganzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuwen","family":"Liu","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Gannan Medical University","place":["Ganzhou, Jiangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Binhui","family":"Xie","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Gannan Medical University","place":["Ganzhou, Jiangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiping","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Innate Immunity and Chronic Inflammatory Diseases, Jiangxi Provincial Department of Education, Gannan Medical University","place":["Ganzhou, China"]},{"name":"Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University","place":["Ganzhou, China"]},{"name":"School of Basic Medicine, Gannan Medical University","place":["Ganzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1651","DOI":"10.1002\/1873-3468.14666","article-title":"Human phytanoyl-CoA dioxygenase domain-containing 1 (PHYHD1) is a putative oxygen sensor associated with RNA and carbohydrate metabolism","volume":"597","author":"Ala-Nisula","year":"2023","journal-title":"FEBS Letters"},{"key":"B2","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1038\/s41586-020-2896-2","article-title":"A reference map of potential determinants for the human serum metabolome","volume":"588","author":"Bar","year":"2020","journal-title":"Nature"},{"key":"B3","doi-asserted-by":"publisher","first-page":"229","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. 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