TDP-43 drives ferroptosis evasion by modulating PCBP1/PCBP2 axis to promote lung adenocarcinoma growth
TL;DR
It is reported that TDP-43 acts as a key ferroptosis regulator facilitating LUAD growth, and whole transcriptome sequencing combined with subsequent validation assays revealed that TDP-43 is capable of suppressing ferroptosis in LUAD cells.
Abstract
Lung adenocarcinoma (LUAD) continues to be one of the top causes of cancer-associated deaths worldwide. TAR DNA-binding protein 43 (TDP-43) has been linked to several tumor-related biological processes, yet its specific role in LUAD growth remains poorly understood. Ferroptosis, an iron-dependent regulated cell death, is increasingly recognized as a key process affecting tumor development. Here, we report that TDP-43 acts as a key ferroptosis regulator facilitating LUAD growth. TDP-43 is upregulated in LUAD tissues and positively correlates with poor patient prognosis. Functionally, TDP-43 silencing impairs LUAD cell proliferation and promotes cell death, whereas TDP-43 overexpression exerts the opposite effects. Consistently, TDP-43 knockdown markedly suppresses xenograft tumor growth in vivo. Whole transcriptome sequencing combined with subsequent validation assays revealed that TDP-43 is capable of suppressing ferroptosis in LUAD cells. Accordingly, TDP-43 silencing sensitizes cells to erastin/RSL3-induced ferroptosis. Mechanistically, TDP-43 exerts its effects through two distinct pathways: it interacts with transcription factor VDR via its C-terminal domain to activate PCBP1 transcription, while directly binding to the UG-rich motif within the 3′UTR of PCBP2 mRNA to stabilize its transcript. Upregulation of iron chaperones PCBP1 and PCBP2 alleviates intracellular Fe2+ overload and lipid peroxidation, allowing LUAD cells to escape ferroptosis and support tumor growth. These results highlight TDP-43's pivotal role in regulating LUAD ferroptosis and offer promising directions for LUAD treatment.