Abstract
Trastuzumab (TRZ) is a primary treatment for HER2-positive (HER2+) breast cancer, but its effectiveness is often limited by drug resistance linked to the PI3K signaling pathway. Capsaicin (CAP), a natural compound from chili peppers, has been shown to block the PI3K/AKT pathway. This study aimed to computationally identify specific gene targets of CAP and clarify its molecular mechanism for overcoming TRZ resistance. Computational analyses was conducted to identify potential capsaicin targets (PTCT), continued the in vitro assay on on TRZ-resistant HCC1954 breast cancer cells including cytotoxicity, cell cycle progression, and mRNA expression levels. We identified 54 genes as PTCT and selected ten as hub genes: EGFR, VEGFA, SRC, TIMP1, FOS, CCND1, TGFB1, ICAM1, EDN1, and PPARA. The combination of CAP and TRZ demonstrated a strong synergistic cytotoxic effect, with a significantly lower IC50 of 3.78 μM compared to 418 μM for CAP alone, confirmed as synergistic by Combination Index analysis (CI = 0.06-0.36), and significantly increase in the Selectivity Index (SI) value to 39.4; an increase in the S and G2/M population, and upregulated the mRNA levels of most hub genes while downregulating SRC and EDN1. In conclusion, CAP effectively reverses TRZ resistance by modulating cell cycle and the transcriptional of specific hub genes. Further research should focus on elucidating the precise molecular mechanisms.Supplementary information
The online version contains supplementary material available at https://doi.org/10.1007/s40203-026-00753-x.