Mechanism of matrine inhibiting retinoblastoma cell growth by downregulating NR1D2 to regulate phosphorylation of the PI3K/AKT signaling pathway.

This study explored the mechanism of matrine-induced apoptosis in human retinoblastoma (RB) cell. Network pharmacology and proteomics approaches were employed to screen the intersection between the pharmacodynamic targets of matrine and the pathogenic targets of RB, and to identify the key signaling pathways underlying the anti-RB effect of matrine. Cytological experiments were used to evaluate cell proliferation, apoptosis, and the expression of PI3K/AKT pathway and apoptosis-related proteins. Results showed matrine inhibited Y79 and WERI-Rb-1 cell growth time- and dose-dependently, suppressed migration, and induced apoptosis. Integrated omics analysis identified Nuclear Receptor Subfamily 1 Group D Member 2 (NR1D2) as a primary responsive target. Matrine markedly downregulated NR1D2 expression at both the mRNA and protein levels. Matrine treatment and NR1D2 interference significantly promoted apoptosis (P < 0.05), while NR1D2 overexpression antagonized the pro-apoptotic effect of matrine. Total PI3K and AKT levels were unchanged, but their phosphorylated forms were altered; matrine-induced apoptosis correlated with Bax, Cleaved Caspase-3 upregulation and Bcl-2 downregulation. Thus, matrine inhibits RB Y79 cell growth by downregulating NR1D2, inhibiting PI3K/AKT phosphorylation and inducing RB cell apoptosis.