The Tumor Suppressor p53 Limits Ferroptosis by Blocking DPP4 Activity

TLDR

Ferroptosis is a regulated cell death that can selectively eliminate tumor cells, and p53 has been shown to promote ferroptosis through transcription‑dependent mechanisms. TP53 limits erastin‑induced ferroptosis by blocking DPP4 activity, and loss of TP53 promotes DPP4‑dependent lipid peroxidation and ferroptosis, revealing a TP53–DPP4 axis that could guide precision therapy for colorectal cancer.

Abstract

Ferroptosis is a form of regulated cell death that may facilitate the selective elimination of tumor cells. The tumor suppressor p53 (TP53) has been demonstrated to promote ferroptosis via a transcription-dependent mechanism. Here, we show that TP53 limits erastin-induced ferroptosis by blocking dipeptidyl-peptidase-4 (DPP4) activity in a transcription-independent manner. Loss of TP53 prevents nuclear accumulation of DPP4 and thus facilitates plasma-membrane-associated DPP4-dependent lipid peroxidation, which finally results in ferroptosis. These findings reveal a direct molecular link between TP53 and DPP4 in the control of lipid metabolism and may provide a precision medicine strategy for the treatment of colorectal cancer by induction of ferroptosis.