SHARPIN, short for SHANK-associated RH domain-interacting protein, is a multifunctional protein. It can form the linear ubiquitin chain assembly complex (LUBAC) with HOIL-1L and HOIP, producing a linear ubiquitin chain connected N-terminal Met1. This complex plays a critical role in NF-κB signaling, inflammation, embryogenesis, and apoptosis. SHARPIN alone also participates in many physiological activities, such as B-cell activation and platelet aggregation [2].

In gene-knockout models, SHARPIN-deficient mice mainly exhibit chronic dermatitis and immunodeficiency with elevated IgM [2]. In humans, biallelic SHARPIN loss of function induces autoinflammation and immunodeficiency, with fibroblasts and B cells showing attenuated canonical NF-κB responses and a propensity for cell death mediated by TNF superfamily members. Secondary lymphoid germinal center B-cell development is substantially reduced [3]. In cancer-related studies, SHARPIN promotes cell proliferation of cholangiocarcinoma and inhibits ferroptosis via the p53/SLC7A11/GPX4 signaling pathway [1]. It also promotes breast cancer progression by controlling important carcinogenic pathways like p53 and ERα [4], and melanoma progression via the Rap1 signaling pathway [5].

In conclusion, SHARPIN is crucial in regulating immune and inflammatory responses, as well as in cancer development. Gene-knockout models in mice and humans have revealed its role in maintaining normal physiological functions and in the pathogenesis of diseases such as autoinflammation, immunodeficiency, and various cancers. Understanding SHARPIN's functions may provide potential therapeutic targets for these diseases.