New player in inflammation-driver liver carcinogenesis: pirin on fire!

Abstract

Pirin (PIR) is a 32 kDa iron-binding protein belonging to the cupin superfamily, with well-recognised roles that include functioning as a transcriptional co-regulator.1 A single ferrous ion (Fe²+) is housed within the N-terminal domain, where it serves as a redox-sensitive allosteric site.2 This iron-binding region is critical for modulating PIR’s conformational dynamics and subcellular localisation in response to fluctuations in the intracellular redox state.3 Under oxidative conditions, PIR undergoes a redox-dependent transition from its reduced Fe²+ (inactive) to oxidized Fe³+ (active) form.3 This conformational change enhances its binding affinity for multiple transcription factors, including nuclear factor I (NF-I), B-cell lymphoma 3-encoded protein and the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) subunits p50 and p65/v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA) amplifying the expression of downstream genes.4 Through these molecular interactions, PIR acts as a key modulator within signaling pathways that regulate inflammation, apoptosis and innate immune responses. The role of PIR has been previously described in several solid tumors, including breast,5 lung,6 colorectal cancers7 and melanoma,8 where PIR has been implicated in promoting cell proliferation and inflammatory signaling. However, until recently, few data were available about the role of PIR in the pathogenesis of hepatocellular carcinoma (HCC). In Gut , Ma et al 9 provide convincing evidence that PIR plays a pivotal role in linking oxidative stress, chronic inflammation and HCC progression (figure 1). The authors demonstrated that PIR expression is progressively upregulated from metabolic dysfunction-associated steatotic liver disease (MASLD), viral hepatitis and cirrhosis to HCC, a pattern confirmed across independent datasets both at the transcriptome and protein levels. Functionally, PIR …