598 A novel curcumin-harmine-isovanillin compound inhibits the growth of actinic keratoses by suppressing MAPK and PI3K-AKT signaling

Actinic keratoses (AK) are premalignant cutaneous lesions with limited treatment options. Here we investigate GZ21T, a novel anti-tumor agent composed of curcumin, harmine, and isovanillin, in the AK. The pro-apoptotic effects GZ21T on EGF-stimulated HaCaT cells were assessed by Annexin-V assay, mechanism was clarified western blot. Treated subjected to RNA-sequencing reverse phase protein array. Differentially expressed genes (DEGs) calculated using DESeq2 for R. Gene set enrichment analysis (GSEA) performed fgsea R, gene variation (GSVA) conducted evaluate GZ21T’s effect pathways implicated pathogenesis Enrichment hypophosphorylated proteins Enrichr. SKH-1 mice exposed UVB (500 J/m2) five times weekly ten weeks subsequently treated 0.25 grams topical or control cream days per week. An increase percentage early (p=0.041) late apoptosis (p=0.029) observed increasing concentrations, which partially mediated PARP cleavage. After 40 days, showed decreased lesion count (p=0.028) tumor surface area (p=0.026). We identified 92 DEGs between HacaT cells, upregulation TP53 NOTCH1 tumor-suppressor genes. GSEA that downregulates KRAS mTOR signaling. GSVA revealed transforming growth factor-beta (TGF-β) secretion NOTCH signaling downregulation MAPK1 3 activation (p<0.05 all). Proteomic demonstrated ErbB, mTOR, HIF-1, PI3K-AKT In conclusion, inhibits AK through suppression targets related MAPK, PI3K-AKT,