P2rx1, a member of the purinergic receptor family, plays crucial roles in multiple biological processes. It is involved in purinergic signaling, which has been linked to various cellular functions such as inflammation regulation and immune cell activation [1,2,3,4,5,6,7,8,9]. Understanding its function can be significantly aided by genetic models like knockout (KO) mouse models.

In pancreatic cancer liver metastasis, a subset of P2RX1-negative neutrophils accumulate, expressing increased immunosuppressive molecules like PD-L1 and enhancing mitochondrial metabolism. Nrf2, a transcription factor, is upregulated in these neutrophils, associated with PD-L1 expression and metabolic reprogramming [1].

In renal ischemia/reperfusion injury, P2RX1 expression is upregulated, and its genetic knockout preserves mitochondrial dynamics by reducing the formation of neutrophil extracellular traps (NETs) as P2RX1-involved metabolic interaction between platelets and neutrophils supports NETs formation [2].

P2rx1 deficiency also alleviates acetaminophen-induced acute liver failure by regulating the STING-TBK1-P65 signaling pathways, inhibiting cell death and promoting inflammation resolution [3].

In acute pancreatitis, genetic ablation or specific antagonism of P2RX1 alleviates inflammatory responses as neutrophil-derived P2RX1 contributes to the inflammation by promoting neutrophil activation through facilitating glycolytic metabolism [4].

In colitis, genetic knockout of P2RX1 suppresses inflammation responses, inhibits neutrophil infiltration, modulates intestinal microbiota, and upregulates the indole alkaloid biogenesis pathway, with the microbiota metabolites-involved aryl hydrocarbon receptor (AhR)/IL-22 axis associated with the beneficial effects [6].

In non-small cell lung cancer, P2RX1-negative neutrophils upregulate PD-L1 expression by inducing fatty acid metabolism, promoting the immunosuppressive microenvironment [7].

In gastric cancer, overexpression of P2RX1 in neutrophils activates the Jak/Stat signaling pathway, suppressing the migration, invasion, and viability of gastric cancer cells and increasing their apoptosis rate, while P2RX1-blocked neutrophils induce CD8+ T cell dysfunction and affect the immune escape of gastric cancer cells [8,9].

In conclusion, P2rx1 is a key player in purinergic signaling, influencing multiple biological processes related to inflammation, immunity, and metabolism. Studies using P2rx1 KO mouse models have revealed its significant roles in diseases such as pancreatic cancer liver metastasis, renal ischemia/reperfusion injury, acetaminophen-induced acute liver failure, acute pancreatitis, colitis, non-small cell lung cancer, and gastric cancer, providing potential therapeutic targets for these diseases.