A selective androgen receptor modulator, S4, displays robust anti-cancer activity on hepatocellular cancer cells by negatively regulating PI3K/AKT/mTOR signalling pathway.

Hepatocellular carcinoma (HCC) is a major global health problem that often correlates with poor prognosis. Due to the insufficient therapy options with limited benefits, it is crucial to identify new therapeutic approaches to overcome HCC. One of the vital signaling pathways in organ homeostasis and male sexual development is Androgen Receptor (AR) signaling. Its activity affects several genes that contribute to cancer characteristics and have essential roles in cell cycle progression, proliferation, angiogenesis, and metastasis. AR signaling has been shown to be misregulated in many cancers, including HCC, suggesting that it might contribute to hepatocarcinogenesis. Targeting AR signaling using anti-androgens, AR inhibitors, or AR-degrading molecules is a powerful and promising strategy to defeat HCC. In this study, AR signaling was targeted by a novel Selective Androgen Receptor Modulator (SARM), S4, in HCC cells to evaluate its potential anti-cancer effect. To date, S4 activity in cancer has not been demonstrated, and our data unrevealed that S4 significantly impaired HCC growth, migration, proliferation, and induced apoptosis through inhibiting PI3K/AKT/mTOR signaling. Since PI3K/AKT/mTOR signaling is frequently activated in HCC and contributes to its aggressiveness and poor prognosis, its negative regulation by the downregulation of critical components via S4 was a prominent finding. Further studies are necessary to investigate the S4 action mechanism and anti-tumorigenic capacity in in-vivo.