Work

DAPK1 orchestrates Lipin1-dependent fatty acid oxidation to enhance ferroptotic susceptibility in colorectal cancer

Year: 2026

Type: article

Abstract: Metabolic reprogramming of lipid metabolism and redox homeostasis critically determines ferroptosis susceptibility in colorectal cancer (CRC), yet the upstream regulatory mechanisms remain unclear. Here, we identify death-associated protein kinase 1 (DAPK1) as a key regulator of Lipin1-dependent lipid metabolism and redox-controlled ferroptosis in CRC. Genetic and pharmacological analyses in CRC cells show that DAPK1 stabilizes Lipin1 and promotes its nuclear localization, thereby enhancing fatty acid oxidation (FAO). DAPK1-driven FAO activation increases lipid peroxidation, disrupts redox balance, and sensitizes CRC cells to ferroptosis, resulting in suppressed cell proliferation and migration. Consistently, DAPK1 overexpression restrains tumor growth in vivo, whereas DAPK1 deficiency accelerates tumor progression. Collectively, these findings reveal the DAPK1–Lipin1–FAO axis as a previously unrecognized metabolic redox vulnerability that can be exploited to induce ferroptosis in CRC.

Source: Cell Death Discovery

DOI: 10.1038/s41420-026-03446-8