Chrysin exacerbates mitophagy-mediated pyroptosis to inhibit the proliferation of hepatocellular carcinoma cells by targeting p53

Primary liver cancer is the third leading cause of cancer-related deaths worldwide. However, current treatments have limited efficacy and high side effects. Chrysin, as a nontoxicity dietary flavonoid polyphenolic compound, has been reported to have significant efficacy in anti-hepatocellular carcinoma (HCC). Nonetheless, its precise mechanism remains unclear. Flow cytometry was employed to detect apoptosis, cell cycle, and mitochondrial membrane potential. RNA-seq was performed to investigate target signaling pathways. Immunofluorescence were utilized to assess the amount and location of target protein, lysosomal function and mitophagy. The results revealed that chrysin effectively suppressed the proliferation of hepatocellular carcinoma cell. RNA-seq analysis unveiled that the signal pathways modulated by chrysin included p53, energy metabolism, mitophagy, and lysosomes. Further experiments confirmed that chrysin inhibited HepG2 cells viability by triggering DNA damage and activating the p53 pathway. Numerous evidence show that p53 regulated the biogenesis of mitochondrial and mitophagy. Similarly, we found that chrysin induced mitochondrial and lysosomal dysfunction, and subsequently blocked mitophagic flux, ultimately triggering GSDME-dependent pyroptosis. Thus, our results implied that chrysin might exacerbate mitophagy mediated pyroptosis to inhibit the proliferation of HCC cells by targeting p53, suggesting that chrysin was a potential alternative drug for the treatment of HCC.

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