ErbB4, also known as HER4, is a member of the ERBB family of receptor tyrosine kinases [3]. It plays well-defined roles in normal tissue development, especially in the heart, nervous system, and mammary gland system. It is activated by ligands like neuregulin 1 (NRG1) and neuregulin 4 (NRG4), and its signaling is involved in multiple pathways that regulate cell proliferation, differentiation, apoptosis, and migration [2,4,6].

Knockout models have demonstrated embryonic lethality due to disrupted heart and brain development, highlighting its crucial role in these processes [2]. In metabolic disorders, studies show that NRG4-ErbB4 signaling is involved in preserving metabolic homeostasis. For example, peripheral NRG4 can act on hypothalamic ErbB4 to excite oxytocin neurons and reduce obesity-related metabolic disorders. Also, NRG4-ErbB4 signaling represses proinflammatory macrophage activity, potentially a target for colitis treatment [4,5,7]. In the context of cancer, ErbB4 seems to have a dual role. While it has growth-inhibiting properties and may act as a tumor suppressor, there are also conflicting data suggesting it can be involved in pro-tumorigenic mechanisms [1,3]. In psoriasis, high expression of ErbB4 in clinical samples promotes psoriasis progression by affecting Th1/Th17 cell differentiation through the IL23/IL17A signal axis [8].

In conclusion, ErbB4 is essential for normal tissue development, especially in the heart and brain. Its role in metabolic disorders and cancer has been increasingly studied. The use of knockout mouse models has been crucial in revealing its functions in these biological processes and disease conditions, providing insights into potential therapeutic targets for related diseases.