Multiplexed transcriptomics to screen drug combination and define therapeutic mechanism of action at single-cell resolution

In this study, we employed the high-throughput single-cell sequencing technology, snHH-seq, to screen clinical drug combinations with anti-hepatocellular carcinoma activity. Single-cell transcriptomics revealed that the combination of HHT and YM155 (HY) exhibited the most potent inhibitory effect on cellular proliferation, which was also validated through in vitro and in vivo functional assays.

Mechanistically, transcription factor regulatory network analysis identified cell type-specific regulators in each subpopulation with HY treatment, and revealed that the anticancer effects primarily target apoptosis-related subpopulations. These findings provide critical insights for precision diagnosis and treatment of hepatocellular carcinoma.