Abstract
Background: Ferroptosis, a regulated form of cell death driven by lipid peroxidation and iron dysregulation, plays a critical role in tumor suppression. The expression of certain genes determine ferroptosis sensitivity and may serve as biomarkers to identify patients who could benefit from ferroptosis-promoting therapies. The role of Methyltransferase-like (METTL) family proteins in colorectal cancer (CRC) tumorigenesis has gained increasing attention, yet the functional relevance of METTL21D (also known as VCPKMT) remains largely unexplored. Methods: CCK8 assays, colony formation assays, and xenograft tumor experiments were used to investigate the role of VCPKMT in proliferation and ferroptosis sensitivity in CRC. RNA sequencing, IP-MS, and RT-qPCR were used to identify the relevant genes of VCPKMT. Co-IP and subcellular fractionation assays, western blotting and immunofluorescence (IF) staining were used to explore the underlying molecular mechanisms of actions of VCPKMT. Results: Herein, we identified that VCPKMT is downregulated in CRC tissues and lower VCPKMT expression correlates with ferroptosis resistance and poorer prognosis. Mechanistically, VCPKMT-induced VCP methylation facilitates its nuclear translocation, a process that enhances VCP's interaction with HDAC1. This interaction promotes the degradation of HDAC1 via the ubiquitin-proteasome pathway, leading to reduced expression of FTH1, a key inhibitor of ferroptosis. Combined targeting of HDAC1 and ferroptosis synergistically suppressed the growth of tumors with low VCPKMT expression. Conclusions: Our findings reveal a novel role for VCPKMT as a regulator of ferroptosis sensitivity in CRC, highlighting the VCPKMT-VCP-HDAC1 axis as a potential therapeutic target for CRC treatment.