ROS-activated SHP-1 signaling underlies artesunate-mediated inhibition of EMT and STAT3-Driven prostate cancer progression.

Constitutive activation of signal transducer and activator of transcription 3 (STAT3) is a hallmark of prostate cancer (PC) progression. Here, we investigated the anticancer effects of artesunate (ART) and its underlying mechanisms in PC. ART selectively reduced the viability of PC cells with minimal toxicity toward normal prostate cells by inducing apoptosis, as evidenced by increased sub-G1 accumulation, Annexin V/propidium iodide (PI)-positive cells, and DNA fragmentation. These effects were mediated by reactive oxygen species (ROS), as glutathione (GSH) and N-acetyl-l-cysteine (NAC) significantly reversed ART-induced cytotoxicity. ART also depleted intracellular GSH and reduced superoxide dismutase (SOD) expression, thereby enhancing oxidative stress. Inhibition of STAT3 by ART was reversed by sodium orthovanadate, implicating protein tyrosine phosphatases (PTPs) in this process. ART downregulated anti-apoptotic B-cell lymphoma-2 (Bcl-2) family proteins, suppressed C-X-C motif chemokine ligand 12 (CXCL12)-induced migration, and inhibited epithelial-mesenchymal transition (EMT) through ROS-dependent activation of Src homology region 2 domain-containing phosphatase-1 (SHP-1). In vivo, ART significantly inhibited prostate tumor xenograft growth, reduced oncogenic protein expression in tumors, and lowered serum interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels. Collectively, ART suppresses PC growth, survival, migration, and EMT by targeting the STAT3 and ROS/SHP-1 signaling pathways, supporting its potential as a therapeutic candidate for PC.