Synergistic effect of Pladienolide B and cisplatin: enhancing autophagy in hepatoma cells through the AMPK/mTOR/ULK1 pathway.

Alternative splicing (AS) is a key driver of development and a major contributor to species diversity. Accumulating evidence indicates its high activity in various cancers. Here, we identified the spliceosome component SF3B1 as a key regulator of cell fate in hepatocellular carcinoma (HCC), with its expression elevated in HCC tissues/cells versus adjacent non-tumor tissues. Using SF3B1 inhibitor Pladienolide B (Pla B), we found that it suppresses HCC cells' proliferation and induces apoptosis. RNA-Seq revealed Pla B modulates AS events in HCC cells; KEGG analysis indicated it affects the AMPK-mTOR pathway to activate autophagy. In vivo xenograft experiments further demonstrated that the combined treatment of Pla B and cisplatin achieved a more potent inhibitory effect on tumor growth compared to either monotherapy. This combinatorial strategy not only reduced tumor cell proliferation and promoted apoptosis but also enhanced autophagy. Collectively, our findings highlight the potential of combining Pla B with cisplatin as a novel and promising therapeutic approach for the treatment of HCC.