Natural product-derived compounds modulating STAT3 signaling in prostate cancer: Mechanistic insights and therapeutic potential

Prostate cancer (PCa) is a major malignancy in men and current treatment options remain limited by therapeutic resistance and treatment-related toxicity. Signal transducer and activator of transcription 3 (STAT3) is a key regulator of PCa progression and an attractive therapeutic target. Natural products provide diverse chemical scaffolds for the discovery of STAT3-targeting agents. This review summarizes natural product-derived compounds that modulate STAT3 signaling in PCa, with a focus on their mechanisms of action, structure-activity relationships, target engagement evidence and translational potential. The reviewed compounds regulate STAT3 signaling through diverse mechanisms, including modulation of upstream kinases, inhibition of STAT3 phosphorylation and nuclear translocation and suppression of STAT3-dependent transcription, thereby affecting PCa cell proliferation, apoptosis, invasion and metastasis. Importantly, the strength of mechanistic evidence varies substantially among compounds, with only a subset supported by direct target engagement approaches, whereas others rely primarily on pathway-level assays or computational predictions. Structural optimization may improve target engagement and selectivity as well as key pharmacological properties, thereby further enhancing their therapeutic potential. However, limited bioavailability, multi-target effects, insufficient in vivo validation and scarce clinical evidence remain major barriers to translation. Overall, natural product-derived STAT3 modulators represent promising leads for PCa therapy, but further rigorous target validation and pharmacological optimization are needed to facilitate their clinical advancement.