Reniformin A Suppresses Triple‐Negative Breast Cancer Progression by Inducing DRP1‐Mediated Mitochondrial Dysfunction and Apoptosis

ABSTRACT Reniformin A (RA) is a natural compound extracted from the medicinal herb Isodon excisoides , known for its tumor‐suppressive properties in lung cancer. Yet, its effects and mechanisms of action in other cancers, such as triple‐negative breast cancer (TNBC), remain unclear. This study aims to investigate the potential effects and underlying molecular mechanisms of RA in TNBC. Here, we demonstrate the significant anti‐cancer activity of RA against TNBC, primarily through the induction of mitochondrial dysfunction and intrinsic apoptosis. Molecular docking and in vitro validation revealed that RA interacts directly with DRP1 at two primary binding sites. This interaction promotes the association of DRP1 with BAX, facilitating their translocation to mitochondria, where they trigger mitochondrial permeabilization, leading to the release of cytochrome c and subsequent apoptosis. Additionally, DRP1 is essential for RA‐induced apoptosis; disruption of the RA‐DRP1 interaction not only impeded the mitochondrial translocation of DRP1 and BAX but also significantly reduced RA's impact on mitochondrial function, apoptosis, and TNBC progression. The inhibition of the RA‐DRP1 interaction also compromised the activation of apoptosis and diminished the effectiveness of RA as a chemotherapeutic agent in vivo. Collectively, these findings suggest that Reniformin A significantly inhibits TNBC by inducing DRP1/BAX‐mediated apoptosis, offering a promising therapeutic strategy for TNBC treatment.