The Nucleoporin NUP188 Enhances Liver Cancer Stemness via POU Class 5 Homeobox 1 Import and SRY-Box Transcription Factor 2 Stabilization.

Liver cancer progression is largely driven by liver cancer stem cells (LCSCs), which possess self-renewal capacity and intrinsic resistance to therapy. Emerging evidence suggests that nuclear pore complexes exhibit cell type-specific compositions that dynamically adapt to different developmental or pathologic contexts. However, whether LCSCs harbor a unique nucleoporin profile that contributes to their stem-like properties remains unclear. In this research, the expression landscape of nucleoporins (NUPs) in LCSCs was explored, and NUP188 was identified as selectively up-regulated in LCSCs. Functional assays demonstrated that NUP188 is essential for maintaining the tumorigenicity, proliferation, and self-renewal capacity of liver cancer cells in vitro as well as in vivo. At the mechanistic level, NUP188 promotes liver cancer progression through two complementary pathways: it facilitates importin-β-mediated nuclear import of POU class 5 homeobox 1, and simultaneously stabilizes SRY-box transcription factor 2 by preventing its lysosome-dependent degradation. These dual mechanisms converge to maintain the stem-like phenotype of LCSCs. Furthermore, a NUP188-targeting peptide was designed that effectively suppressed tumor sphere formation and proliferative capacity of liver cancer cells in vitro and inhibited tumor growth in vivo, without detectable systemic toxicity. In summary, these findings emphasize NUP188 as a key modulator of LCSC stemness and liver cancer progression, highlighting it as an attractive target for therapeutic intervention in liver cancer.