Peptide‑based therapeutics targeting the SLC39A14‑PIWIL2 fusion in hepatocellular carcinoma.

Fusion genes are key oncogenic drivers in various cancers; however, their role in hepatocellular carcinoma (HCC) remains underexplored. Here, we analyzed RNA-seq data from 68 HCC patients and identified several fusion products where SLC39A14-PIWIL2 stood out a putative driver. Functional assays revealed that the promoter of SLC39A14 potentially drives the overexpression of a truncated PIWIL2 protein (tPIWIL2), which retains its oncogenic MID and PIWI domains, in liver tissues. Both the wild-type and tPIWIL2 were found to interact with oncogenic partners HDAC3 and NME2 through these domains, as demonstrated by structural modeling and molecular dynamics simulations. To disrupt these interactions, we designed novel decoy peptides that potentially competes with both HDAC3 and NME2, effectively inhibiting PIWIL2-driven tumor activity in Huh7, HepG2, SNU449, and SNU398 HCC cell lines. Among the tested candidates, NEP1 markedly suppressed PIWIL2-driven oncogenic activity, and its co-administration with 5-fluorouracil (5-FU) significantly reduced PIWIL2-induced chemoresistance, thereby enhancing therapeutic efficacy. Collectively, these findings establish SLC39A14-PIWIL2 as a novel oncogenic fusion in HCC and highlight fusion protein-targeted peptide therapeutics as a promising avenue for precision treatment in HCC.