Hepatic micropeptide modulates mitochondrial RNA processing machinery in hepatocellular carcinoma

Micropeptides, originating from noncanonical translation, represent novel biomolecules with critical roles in tissue homeostasis and cancer development. However, the proteomic landscape and functional mechanisms of micropeptides in hepatocellular carcinoma (HCC) remain largely elusive. By employing a newly devised ultrafiltration tandem mass spectrometry assay, we identified an abundance of micropeptides in clinical HCC samples. Among them, a long non-coding RNA (lncRNA)-derived micropeptide mitochondrial RNase P inhibitory peptide (MRPIP) attenuated HCC progression by modulating the mitochondrial RNA processing machinery. Mechanistically, energy-stress-induced MRPIP hindered mitochondrial ribonuclease P (mtRNase P) complex assembly by interacting with HSD17B10 at the R25 residue, which disrupted the HSD17B10 tetramerization and the subsequent HSD17B10-TRMT10C subcomplex formation, leading to perturbed post-transcriptional RNA processing, translation, energy production in mitochondria, and suppressed cancer progression. Strikingly, the 20-aa functional peptide generated from MRPIP sequences robustly inhibited HCC progression in vitro and in vivo. Overall, our study uncovered and characterized a class of HCC-associated micropeptides, shedding light on cancer diagnosis and treatment.