HERVH-derived eRNA activates a super-enhancer-driven ALDH1A3/SAT1 axis to promote ferroptosis escape and pancreatic cancer development.

Endogenous retroviruses (ERVs), widely distributed in the human genome, are usually epigenetically silenced but can be reactivated in cancer. Activated ERVs may act as regulatory elements or produce noncoding RNAs that modulate gene expression and affect tumor biology. Their role in pancreatic ductal adenocarcinoma (PDAC), particularly in ferroptosis regulation, remains unclear. Here, we identify human endogenous retrovirus-H (HERVH) derived enhancer RNAs (eRNAs) aberrantly overexpressed in PDAC by integrating gene expression and histone modification data. Silencing HERVH markedly suppresses PDAC proliferation and tumor growth. Mechanistically, HERVH transcription is driven by the super-enhancer-associated transcription factor Krüppel-like factor 5 (KLF5), and HERVH eRNAs cooperate with KLF5 to transactivate a distal super-enhancer upstream of aldehyde dehydrogenase family 1 member 3 (ALDH1A3), increasing its expression. ALDH1A3 inhibits the reactive oxygen species/specificity protein 1/spermidine/spermine N1-acetyltransferase 1 (ROS/Sp1/SAT1) cascade, reducing lipid peroxidation and ferroptosis. Disrupting this axis induces ferroptotic death and impairs PDAC development. Our study reveals a previously unrecognized mechanism in which HERVH-derived eRNAs regulate ferroptosis via super-enhancer-mediated transcriptional reprogramming and highlights the KLF5/HERVH/ALDH1A3 pathway as a potential therapeutic target in PDAC.