Peli1, short for Pellino E3 Ubiquitin Protein Ligase 1, is an E3 ubiquitin ligase. It serves as a key regulator in inflammation, autoimmunity, and various signaling pathways, such as the NF-κB and AP-1 pathways. Peli1's functions impact multiple biological processes, making it of great biological importance. Genetic models, like gene knockout (KO) and conditional knockout (CKO) mouse models, are valuable tools for studying Peli1 [1-9].

In cardiac fibrosis, CM-conditional deletion of Peli1 improved pressure overload-induced fibrosis. Exosomes from mechanical stretch-induced WT CMs promoted cardiac fibroblast activation, while Peli1-/-MS-Exos reversed this effect. Peli1 promoted miR-494-3p expression via NF-κB/AP-1 in CMs, which then induced CFs activation [1].

In pancreatic cancer, PELI1 is overexpressed, increases ubiquitination of RPS3, activates the PI3K/Akt/GSK3β signaling pathway, reduces p53 protein stability, and promotes cancer progression [2].

In breast cancer, EGFR activation leads to PELI1 phosphorylation, enhancing its E3 ubiquitin ligase activity, and PELI1 in turn stabilizes EGFR, promoting metastasis [3].

Peli1-deficient mice have alleviated peritonitis and increased resistance to LPS endotoxin shock, as Peli1 is required for NLRP3-induced caspase-1 activation and IL-1β maturation [4].

Macrophage Peli1 deletion in mice reduces M1 macrophage polarization, myocardial infarct size, and improves cardiac function in myocardial ischemia/reperfusion injury [5].

Peli1-/-mice show better learning and memory and lower cytokine levels after methamphetamine exposure, suggesting the Peli1-RIPK1 axis is involved in neuroinflammation [6].

In esophageal squamous cancer, PELI1 promotes radiotherapy sensitivity by inhibiting noncanonical NF-κB [7].

Peli1-deficient mice are protected from psoriasiform dermatitis, with reduced IL-17A production [8].

ZIKV-infected pregnant mice lacking Peli1 signaling have reduced placental inflammation and congenital abnormalities [9].

In conclusion, Peli1 is a crucial E3 ubiquitin ligase involved in multiple biological processes and diseases. Studies using KO and CKO mouse models have revealed its roles in cardiac fibrosis, cancer progression, inflammation, and neurodegenerative and infectious diseases, providing insights into potential therapeutic targets for these conditions.