Curcumin suppresses HNSCC tumorigenesis through directly targeting FOSL1/JUN

Natural products and affordable herbal medications have emerged as promising alternatives for cancer therapy, particularly for patients with limited access to standard treatments. Among these, curcumin, the bioactive polyphenol from Curcuma longa (turmeric), has shown broad anti-cancer potential. However, its molecular mechanism remains poorly defined, especially for head and neck squamous cell carcinoma (HNSCC). Here, we identify curcumin as a potent inhibitor of HNSCC tumorigenesis and explored its underlying mechanism. Comparative analyses of three anti-cancer natural products, including curcumin, gingerol, and allicin, revealed that only curcumin robustly inhibited HNSCC cell proliferation, invasion, and cancer stem cell self-renewal, with potency comparable or superior to cisplatin. Transcriptomic and Gene Set Enrichment Analyses demonstrated that curcumin significantly suppressed FOSL1/AP-1 signaling, a well-known key oncogenic signaling that promotes malignant progression of HNSCC. Biophysical and biochemical assays showed that curcumin directly binds to the FOSL1/JUN heterodimer (Kd ≈ 10 μM), disrupting its DNA-binding activity. In agree with this finding, chromatin immunoprecipitation confirmed that curcumin inhibited FOSL1/JUN recruitment to promoter of cancer stem cell marker gene BMI1, as well as super-enhancer-associated oncogenic loci such as MET, EGFR and TP63. At last, curcumin treatment profoundly suppressed HNSCC tumor growth in xenograft model and exhibited superior efficacy compared with the FOSL1/AP-1 inhibitor T-5224, without apparent toxicity. Collectively, our findings identify FOSL1/JUN complex as a direct molecular target of curcumin and uncover a novel mechanism by which this accessible natural product suppresses HNSCC tumorigenesis, supporting its potential as an affordable and safe therapeutic option for cancer treatment.