PANapoptosis Elicited by Advanced Bismuth-Based Anticancer Drugs through Oxidative Damage

Tetramethylpyrazine (TMP) demonstrates significant anticancer activity; however, its clinical application is limited by poor water solubility and low bioavailability. To address this, a bismuth-based metal complex (TMP-Bi) was formed by combining TMP with bismuth. Both in vitro and in vivo experiments demonstrated that TMP-Bi significantly enhances the anticancer effect, inducing PANoptosis in cancer cells. TMP-Bi generates high levels of reactive oxygen species, causing mitochondrial damage and triggering endogenous apoptosis. Furthermore, it activates the pyroptosis pathway by cleaving GSDMD-F into GSDMD-N. It also upregulates caspase-1 and NF-κB proteins and increases lactate dehydrogenase release. These findings, consistent with those of Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis, revealed that TMP-Bi treatment affected key biological processes including the calcium signaling pathway, tumor necrosis factor response, inflammatory response, and apoptosis. Crucially, the low toxicity and good biocompatibility of bismuth contribute significantly to this complex, making TMP-Bi a promising candidate for cancer treatment.