Abstract

Abstract Background Aberrantly activated super‐enhancers (SEs) drive hepatocellular carcinoma (HCC) malignancy. However, the sustained oncogenic mechanisms mediated by SE‐driven genes remain elusive. Methods HCC‐specific SE genes were identified by cross‐analysing H3K27ac ChIP‐seq and RNA sequencing (RNA‐seq). Analyses of HCC databases using Cox proportional hazards regression were performed to identify core SE‐activated genes. The SE‐mediated transcriptional activation of an identified gene (i.e., KIAA1522) was validated through SE landscapes, ChIP‑qPCR, CRISPR interference and dual‑luciferase reporter assays. HCC cells with knockdown or overexpression of KIAA1522 were constructed to evaluate its functional impact, and RNA‐seq was performed to identify downstream pathways. Ferroptosis was evaluated by measuring the levels of malondialdehyde (MDA), reactive oxygen species (ROS) and ferrous ions. Results SE inhibitors suppressed HCC cell proliferation. KIAA1522 was identified as an HCC‐specific 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: 32753965‒32762956 transcriptionally activated KIAA1522. Functionally, KIAA1522 knockdown exerted anti‐proliferative 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.