Abstract

Signal transducer and activator of transcription 3 (STAT3) drives multiple hallmarks of tumorigenesis, making it a validated therapeutic target for diverse cancers. The 1,4-naphthoquinones, such as plumbagin (PL), exhibit anticancer activity via inhibiting STAT3 phosphorylation and dimerization, but their severe cytotoxicity precludes clinical translation. Here, we screened 23 PL derivatives for STAT3 inhibitory activity and normal cell cytotoxicity, identifying III-1a as the optimal candidate with superior STAT3 inhibition and reduced toxicity compared to PL. Molecular docking and cellular thermal shift assay (CTESA) revealed that III-1a binds to the L244 residue within the coiled-coil domain (CCD) of STAT3. In vitro, III-1a dose-dependently suppressed JAK/STAT3 signaling in oral squamous cell carcinoma (OSCC), particularly STAT3 Ser727 phosphorylation. It inhibited STAT3-mediated epithelial-–mesenchymal transition (EMT) and induced ferroptosis, thereby attenuating OSCC proliferation, invasion and migration. STAT3 knockdown abrogated its anti-tumor effects, and in vivo studies further confirmed its efficacy against OSCC growth. Collectively, this study identifies a novel PL-derived STAT3 inhibitor targeting STAT3 CCD to regulate EMT and ferroptosis, providing a promising therapeutic candidate for OSCC.

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