Targeting PABPC1: A therapeutic strategy of natural Ganoderma meroterpenoid LZ22 against triple-negative breast cancer proliferation

Triple-negative breast cancer (TNBC) is characterized by marked heterogeneity and is associated with a high recurrence risk. Current therapeutic approaches for TNBC remain heavily reliant on chemotherapy, with limited treatment options available. PABPC1, a highly conserved member of the poly(A)-binding protein family, plays a critical role in regulating mRNA stability and translation. Aberrant expression of PABPC1 in various cancers suggests its potential involvement in TNBC pathogenesis. In this study, we demonstrated that LZ22 a natural Ganoderma meroterpenoid, effectively inhibits the proliferation of TNBC cells. Using a chemical proteomics strategy, we identified PABPC1 as a key target mediating LZ22's anti-TNBC activity. It has been confirmed that natural meroterpenoid significantly regulate the PABPC1 downstream signaling pathway, thereby downregulating the expression of pathway-related proteins such as CDK14 and NR4A3. Furthermore, through structural optimization of LZ22 guided by molecular docking, we identified a derivative (LZ22-4) with enhanced anti-tumor proliferative activity. These findings not only identify PABPC1 as a valuable therapeutic target for TNBC but also provide new opportunities and novel insights for advancing anti-TNBC drug development with LZ22 as a potential drug leading compound.