Water extract of sporoderm-broken spores of Ganoderma lucidum elicits dual antitumor effects by inhibiting p-STAT3/PD-L1 and promoting ferroptosis in castration-resistant prostate cancer

Prostate cancer (PCa) is one of the most common malignancies among male patients with cancer pathology worldwide. Owing to the inevitable development of irremediable castration-resistant prostate cancer (CRPC) following intervention with androgen deprivation therapy, new therapeutic strategies are in great demand. Ganoderma lucidum, a medicinal fungus, has recently been reported to be a potential antitumor agent. However, whether the water extract of sporoderm-broken spores of G. lucidum (BSGWE), a special approach to obtain whole wall-broken spore extracts of G. lucidum, can inhibit castration-resistant prostate cancer (CRPC) has not been well characterized. In this study, we found that BSGWE inhibited cell proliferation, caused cell cycle arrest in G2/M phase, and promoted ferroptosis, which resulted in high levels of reactive oxygen species (ROS) in vitro and suppressed the growth of CRPC tumors in xenograft models. In addition, we reported that BSGWE inhibited STAT3 expression, which partly accounted for the inhibition of the transcription of PD-L1 and led to ferroptosis, manifested by the downregulation of SLC7A11 and GPX4 expression. Furthermore, BSGWE exhibited a synergistic effect with 5-fluorouracil (5-Fu) in chemotherapy of CRPC in vitro and in vivo. This study provides biological evidence that BSGWE is a novel STAT3 inhibitor that exerts anti-proliferation, pro-cell death, and pro-immunity effect and indicates a novel utilization of BSGWE in neoadjuvant chemotherapy of CRPC