Rapamycin targetome mining identifies RBBP7 as a druggable epigenetic vulnerability in hepatocellular carcinoma.

Zan Gao Le Sun Jian-Long Li Heng Lv Ying-Nan You Kun Wang Nan Su Lin Wang Nan Liu Jun-Hao Hu Hong Jiang Bing Shan Yao-Yang Zhang

Sep 2026 · Cell Chemical Biology · 0 citations · 56 references

Medicine

Abstract

Identifying therapeutic protein targets is challenging due to unpredictable druggability. Exploring multi-purpose drug targetomes, such as that of rapamycin, offers a valuable strategy for target discovery. Here, using chemical proteomics, we identified the histone-binding protein RBBP7 as a previously unrecognized target of rapamycin. Rapamycin disrupts the RBBP7-H4 interaction, leading to reduced histone H4 acetylation and downregulation of DNMT1. Based on this mechanism, we designed RBBP7-targeting peptides (RBBP7-TPs). RBBP7-TP4 exhibited potent anti-tumor activity in both cellular and xenograft mouse models of hepatocellular carcinoma (HCC). Furthermore, RBBP7-TP4 synergized with HDAC inhibitors to enhance epigenetic efficacy in HCC models, supporting a promising combination strategy. Collectively, our findings highlight the value of mining multi-purpose drug targetomes for therapeutic target discovery. RBBP7 is established as a druggable target in cancer, and RBBP7-TP4 represents a potential peptide-based therapeutic candidate.

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