LFPM Inhibition of RING1-Mediated p53R175H Degradation Drives Oncogenesis in p53R175H-Mutant Cancers

The p53R175H mutant, a prevalent hotspot mutation in the p53 tumor suppressor gene, is linked to adverse clinical outcomes due to its gain-of-function properties in malignancies. Despite high expression levels of p53R175H protein in human cancers, the underlying mechanisms for its accumulation remain inadequately understood. Here, we identify a previously uncharacterized long non-coding RNA, designated as LFPM, which specifically interacts with p53R175H, excluding the wild-type p53, and modulates its protein stability. The interaction occurs via the DNA-binding domain of p53R175H and a specific loop region within LFPM. By stabilizing p53R175H, LFPM enhances its gain-of-function phenotypes, including augmented cellular proliferation and ferroptosis resistance. Mechanistically, LFPM disrupts the RING1-p53R175H interaction, thereby inhibiting RING1-mediated ubiquitination and subsequent proteasomal degradation of p53R175H. Clinically, elevated LFPM expression is associated with poorer survival outcomes in tumors harboring p53R175H mutations. Our findings suggest that targeting the LEFM-p53R175H axis may offer a therapeutic strategy for cancers with p53R175H mutations. These findings underscore the therapeutic potential of targeting the LFPM-p53R175H axis in p53R175H-mutant cancers, positioning LFPM as both a biomarker and a viable therapeutic target.