Deciphering\nthe Comprehensive Structure–Activity\nRelationship of Sunshinamide for Breast Cancer Therapy through Dual\nModulation of Apoptotic and Ferroptotic Pathways via TrxR1 and Gpx4\nInhibition

Sunshinamide, a cyclodepsipeptide, has demonstrated significant\npotential in inhibiting cancer cell proliferation. Our prior research\nestablished the total synthesis and anticancer properties of sunshinamide.\nHowever, a deeper understanding of the structure–activity relationship\n(SAR) of sunshinamide remained imperative. In this study, we aimed\nto elucidate the SAR and mechanistic insights underlying sunshinamide\naction, both in vitro and in vivo. SAR studies confirm the crucial\nroles of both the bicyclic-ring and disulfide moiety in the anticancer\nactivity of sunshinamide. Our recent findings unveil that sunshinamide\ntargets TrxR1, leading to ROS generation and ER-stress-mediated apoptosis,\nwhile also promoting lipid peroxidation by targeting Gpx4, rendering\ncancer cells vulnerable to ferroptosis. In vivo, experiments demonstrated\nthe effectiveness of sunshinamide in reducing tumor growth by inducing\nboth apoptosis and ferroptosis. The dual efficacy of sunshinamide\nin eliciting apoptosis and ferroptosis positions it as a promising\ncandidate for breast cancer therapy, addressing the challenge of chemoresistance.