A. membranaceus is a
traditional Chinese medicine that regulates
blood sugar levels, suppresses
inflammation, protects the liver, and enhances immunity. In addition, A. membranaceus is also widely used in
diet therapy and is a well-known health tonic.
Formononetin is a natural product isolated from A. membranaceus that has multiple biological functions, including anti-
cancer activity. However, the mechanism by which
formononetin inhibits
tumor growth is not fully understood. In this present study, we demonstrated that
formononetin suppresses
PD-L1 protein synthesis via reduction of MYC and
STAT3 protein expression. Furthermore,
formononetin markedly reduced the expression of MYC
protein via the RAS/ERK signaling pathway and inhibited STAT3 activation through JAK1/STAT3 pathway. Co-immunoprecipitation experiments illustrated that
formononetin suppresses
protein expression of PD-L1 by interfering with the interaction between MYC and STAT3. Meanwhile,
formononetin promoted
PD-L1 protein degradation via TFEB and TFE3-mediated lysosome biogenesis. T cell killing assay revealed that
formononetin could enhance the activity of cytotoxic T lymphocytes (CTLs) and restore ability to kill
tumor cells in a co-culture system of T cells and
tumor cells. In addition,
formononetin inhibited cell proliferation, tube formation, cell migration, and promoted
tumor cell apoptosis by suppressing PD-L1. Finally, the inhibitory effect of
formononetin on
tumor growth was confirmed in a murine xenograft model. The present study revealed the anti-
tumor potential of
formononetin, and the findings should support further research and development of anti-
cancer drugs for
cervical cancer.