A novel peptide interacts with RPL8 to alleviate portal hypertension by promoting ferroptosis

Abstract

Liver fibrosis and mortal consequence of portal hypertension (PHT) is driven by hepatic stellate cells (HSCs) activation and their limited-explored property against elimination. We uncovered that HSC activation decreased the sensitivity to ferroptosis. By Ribo-seq, we identified an unannotated 57-amino-acid ferroptosis-associated peptide (FAP) from LOC102548472-201. Upon activation, HSCs underwent a marked reduction in FAP translation, which was subsequently restored in response to ferroptosis inducer. In contrast to the ferroptotic resistance of HSCs based on LOC102548472-201 loss, reintroducing FAP led to upregulation in ferroptosis, whereas the mutant construct of FAP exerted a counteracting role. In vivo , FAP overexpression attenuated HSC activation, collagen deposition, liver injury, and portal hypertension, accompanied by enhanced ferroptosis level. Mechanistically, FAP directly interacted with the ribosomal protein RPL8 and promoted its redistribution into translationally active polysomes, thereby selectively reprogramming the translation of ferroptosis-associated transcripts, including JUN and NQO1, ultimately facilitating ferroptosis. These findings identify FAP as a novel peptide that promotes HSC ferroptosis through FAP–RPL8 axis to attenuate liver fibrosis and PHT, providing potential target for clinical therapy.