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However, the sustained oncogenic mechanisms mediated by SE\u2010driven genes remain elusive.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>HCC\u2010specific SE genes were identified by cross\u2010analysing H3K27ac ChIP\u2010seq and RNA sequencing (RNA\u2010seq). Analyses of HCC databases using Cox proportional hazards regression were performed to identify core SE\u2010activated genes. The SE\u2010mediated transcriptional activation of an identified gene (i.e., KIAA1522) was validated through SE landscapes, ChIP\u2011qPCR, CRISPR interference and dual\u2011luciferase reporter assays. HCC cells with knockdown or overexpression of KIAA1522 were constructed to evaluate its functional impact, and RNA\u2010seq was performed to identify downstream pathways. Ferroptosis was evaluated by measuring the levels of malondialdehyde (MDA), reactive oxygen species (ROS) and ferrous ions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>SE inhibitors suppressed HCC cell proliferation. KIAA1522 was identified as an HCC\u2010specific SE gene, exhibiting elevated expression in HCC tissues and an association with unfavourable outcomes. Targeting SEs reduced KIAA1522 expression, and the SE region at chr1: 32753965\u201232762956 transcriptionally activated KIAA1522. Functionally, KIAA1522 knockdown exerted\u00a0anti\u2010proliferative effects in vitro and in vivo. Furthermore, its knockdown triggered ferroptosis, elevated the levels of MDA, ROS and ferrous ions, and downregulated the expression of hallmark proteins. Conversely, KIAA1522 overexpression reversed these effects. Notably, targeting the SEs recapitulated the phenotypic consequences of KIAA1522 knockdown. Mechanistically, activating transcription factor 4 (ATF4) serves as a key downstream effector of KIAA1522, playing an essential role in ferroptosis triggered by KIAA1522 knockdown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>As a SE\u2010driven oncogene, KIAA1522 facilitates HCC progression via evasion of ferroptosis, representing an actionable target with potential for clinical translation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Aberrantly activated SEs drive the overexpression of the oncogene KIAA1522 in HCC.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Targeting SEs and knocking down KIAA1522 facilitate ferroptosis in HCC.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>As a key downstream effector of KIAA1522, ATF4 plays an essential regulatory role in ferroptosis mediated by the oncoprotein.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ctm2.70710","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T05:14:18Z","timestamp":1781241258000},"source":"Crossref","is-referenced-by-count":2,"title":["Super\u2010enhancer\u2010driven KIAA1522 upregulation suppresses ferroptosis in hepatocellular carcinoma"],"prefix":"10.1002","volume":"16","author":[{"given":"Xinyang","family":"Li","sequence":"first","affiliation":[{"name":"Henan Key Laboratory of Cancer Epigenetics Cancer Institute The 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