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LFPM inhibition of RING1-mediated p53R175H degradation drives oncogenesis in p53R175H-mutant cancers
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DOI：10.1038/s41418-026-01805-7.png)
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Abstract
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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 binds to the L2 loop of p53R175H via a defined loop domain, thereby stabilizing the oncoprotein. Notably, wild-type p53 suppresses LFPM transcription, whereas p53R175H escapes this repression, establishing a pathogenic positive feedback loop. Functionally, LFPM promotes p53R175H-driven tumorigenesis by enhancing cellular proliferation and ferroptosis resistance. Mechanistically, LFPM competitively disrupts the interaction between p53R175H and the E3 ubiquitin ligase RING1, thus shielding p53R175H from ubiquitin-mediated degradation. Clinically, elevated LFPM expression correlates with poorer survival, specifically in p53R175H-mutant cancers. Our work unveils a pivotal mechanism for mutant p53 stabilization and nominates the LFPM-p53R175H axis as a promising therapeutic target.
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