Chrm4, also known as cholinergic receptor muscarinic 4, is a G-protein-coupled receptor. It is involved in various biological processes. In the cholinergic system, it plays a role in cell-to-cell communication, and its associated pathways may include those related to cytokine regulation and cell signaling cascades. Understanding its function is crucial as it is implicated in multiple physiological and pathological conditions [1-10].

In prostate cancer, Chrm4 has been extensively studied. After androgen-deprivation therapy (ADT), Chrm4 is highly expressed in prostate cancer cells. Overexpression of Chrm4 can drive neuroendocrine differentiation of prostate cancer cells. Mechanistically, Chrm4-driven AKT/MYCN signaling upregulates interferon alpha 17 (IFNA17) in the tumor microenvironment (TME) after ADT, which in turn mediates a feedback mechanism to activate the immune checkpoint pathway and promote neuroendocrine differentiation [1]. Also, nerve growth factor (NGF) interacts with Chrm4 after ADT, and this interaction regulates neuroendocrine prostate cancer (NEPC) differentiation. Pharmacologic NGF blockade and NGF knockdown can inhibit Chrm4-mediated NEPC differentiation and AKT-MYCN signaling activation [2]. Additionally, in prostate cancer, the interaction between interleukin-1 receptor antagonist (IL1RN) and Chrm4 after ADT activates the MAPK/AKT signaling pathway, promoting immunosuppression and neuroendocrine differentiation [3].

In conclusion, Chrm4 plays a significant role in the development and progression of prostate cancer, especially in the context of neuroendocrine differentiation and associated immunosuppressive responses. Studies on Chrm4 in prostate cancer, including those potentially using gene knockout or conditional knockout mouse models (implied by in-vivo functional studies), have provided insights into its role in this disease area, highlighting its potential as a therapeutic target for NEPC [1-4].