Berberine and Etoposide Exert Synergistic Anticancer Effects in A431 Epidermoid Carcinoma Cells

Berberine, a natural isoquinoline alkaloid derived fromCoptidis rhizoma has long been used in traditional medicine and has recently attracted attention for its potential role in cancer therapy. Emerging evidence suggests that berberine can inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of lipid metabolism that has also been implicated in tumor biology. While the role of PCSK9 in cardiovascular diseases is well established, its contribution to cancer progression and therapeutic response remains incompletely understood. Here, we investigated whether berberine-mediated inhibition of PCSK9 could enhance the efficacy of chemotherapeutic agents. Berberine reduced PCSK9 expression at both mRNA and protein levels and increased LDLR abundance in A431 cells, which exhibit high basal PCSK9 expression. Functionally, berberine decreased cell viability in a dose-dependent manner and exhibited a strong synergistic interaction with etoposide, according to the HSA synergy score. Mechanistic analyses indicated that berberine enhances etoposide-induced cytotoxicity, at least in part by delaying the resolution of DNA-damage associated signals. Importantly, genetic silencing of PCSK9 recapitulated the sensitizing effect of berberine, while palmatine, a structurally related compound with lower efficacy in reducing PCSK9 levels, showed decreased synergy with etoposide, although evaluated under a different range of concentrations. Collectively, these findings support a role for PCSK9 in modulating cellular sensitivity to etoposide and suggest that berberine may act as a potential adjuvant in this context.