A novel tetramethylpyrazine derivative inhibits thyroid cancer progression by epigenetically activating the DUSP19-mediated JNK signaling pathway

<p indent="0mm">Newly synthesized derivatives based on ligustrazine (TMP) demonstrate superior anticancer effects and reduced adverse effects. However, the efficacy and mechanism of the most potent TMP derivatives against thyroid cancer (TC) remain unclear. Through a mini screening, we identify the TMP-based dimeric compound 8e as exhibiting the strongest anti-tumor effect against TC. We further demonstrate that 8e impedes TC progression primarily by inhibiting proliferation and inducing apoptosis, while showing minimal cytotoxicity in normal human thyroid epithelial cells and negligible impact on visceral organs in nude mice, confirming its safety. Mechanistically, 8e regulates H3K27 and H3K18 acetylation of the DUSP19 promoter in a p300-independent manner, thereby activating the DUSP19-pJNK axis to slow TC progression. Furthermore, combination treatment with 8e and the histone acetyltransferase P300 inhibitor C646 synergistically suppresses TC development both <italic>in vitro</italic> and <italic>in vivo</italic> with minimal toxicity. Our data identify 8e as a highly promising and hypotoxic epigenetic inhibitor and apoptotic agent, and suggest that 8e/C646 combination therapy holds significant potential as a novel therapeutic strategy for advanced TC patients.