Neuregulin 4 in Insulin Resistance: Mechanisms, Controversies, and Therapeutic Perspectives.

Neuregulin 4 (Nrg4) is an adipocyte-secreted factor belonging to the epidermal growth factor (EGF) family, and has been implicated in the regulation of metabolic homeostasis, particularly insulin resistance (IR). Preclinical studies have demonstrated that Nrg4 activates ErbB4 receptor tyrosine kinase and downstream signaling pathways such as PI3K/AKT and AMPK/mTOR, leading to inhibition of inflammatory responses, regulation of autophagy, and protection of mitochondrial function, all of which can ameliorate IR in animal models. However, clinical evidence regarding Nrg4's association with insulin sensitivity in humans remains inconsistent and even contradictory. While some studies report reduced circulating Nrg4 levels in patients with type 2 diabetes and a positive correlation with insulin sensitivity, others have found a negative correlation, suggesting that Nrg4 may play context-dependent or even opposing roles. This review aims to provide a comprehensive overview of the physiological characteristics and signaling mechanisms of Nrg4, critically evaluate the evidence for its role in improving IR, and explicitly address the existing discrepancies between preclinical and clinical findings. Finally, we discuss the therapeutic potential and safety considerations of targeting Nrg4 for IR and related metabolic diseases, acknowledging the current limitations and unresolved controversies.