Nuclear Pirin promotes HCC by acting as a key inflammation-facilitating factor
Menée à l'aide de lignées cellulaires de carcinome hépatocellulaire et de modèles murins, cette étude met en évidence un mécanisme par lequel la pyrine nucléaire favorise le processus inflammatoire et la progression tumorale
Background : Chronic inflammation and elevated reactive oxygen species are key contributors to hepatocellular carcinoma (HCC) progression.
Objective : This study aims to investigate the role of the oxidative stress sensor protein Pirin (PIR) as a critical mediator of inflammation in HCC progression.
Design : We investigated PIR’s role in HCC tumourigenesis through RNA interference, genetic knockout and pharmaceutical inhibition in HCC cell lines and various mouse models. Furthermore, we used transcriptomics, quantitative reverse transcription PCR, western blot, immunofluorescence staining and immunohistochemistry analysis to elucidate the molecular details.
Results : This study reveals a novel redox-dependent mechanism governing PIR’s nuclear shuttling, contributing to liver inflammation and HCC progression. We identified a positive feedback axis where nuclear PIR amplifies inflammatory responses, leading to hepatitis and HCC advancement. Cytokines in this loop are regulated by PIR-enhanced v-rel reticuloendotheliosis viral oncogene homolog A (RELA) transcription, promoting PIR’s nuclear translocation, increasing proinflammatory cytokine levels, and disrupting redox balance. We confirmed that liver parenchymal cells produce autocrine cytokines supporting their growth and malignancy. Notably, PIR’s redox-mediated nuclear shift can be inhibited by N-acetyl cysteine or PIR inhibitors, reducing HCC promotion in mice.
Conclusion : We elucidate a novel redox-dependent regulatory mechanism governing the nuclear localisation of PIR and its role in promoting liver inflammation and HCC progression. Our findings underscore the significance of cellular redox status in regulating PIR’s activity and highlight the potential of targeting this pathway with antioxidants to mitigate HCC progression.
Gut , article en libre accès, 2025