80 Quick summary: This study identifies the adipokine neuregulin 4 as a critical suppressor of breast cancer metastasis that functions by deactivating the molecular pathways responsible for tumour cell invasion. Findings reveal that obesity reduces the levels of this protective protein in adipose tissue, thereby removing a natural barrier against cancer spread and increasing the risk of poor clinical outcomes. These insights offer a clear direction for public policy and healthcare practice to prioritise metabolic health, while simultaneously highlighting the therapeutic potential of targeting the NRG4–ERBB4 signalling axis to improve patient survival and long term well being. In a recent study published in Genes & Diseases, researchers from Nanjing Medical University, East China Normal University, and Shanghai Sixth People’s Hospital Affiliated with Shanghai Jiao Tong University School of Medicine investigated the role of the adipokine neuregulin 4 (NRG4), a member of the neurotrophic factor family, in suppressing metastatic dissemination and delineated the underlying molecular mechanisms involving ERBB4–YAP1 signalling. Using MMTV-PyMT and 4T1 breast cancer models, the researchers demonstrated that while obesity typically facilitates metastatic progression, NRG4—an adipokine secreted by inguinal white adipose tissue (iWAT)—functions as a potent suppressor of cancer cell migration and epithelial–mesenchymal transition (EMT). Proteomic analysis of the adipocyte secretome revealed that NRG4 expression is markedly reduced in the iWAT of obese subjects, highlighting the crucial role of adipose-derived factors in modulating the tumour microenvironment through paracrine signalling. Single-cell transcriptomic data further corroborated these findings, showing a notable inverse association between NRG4 expression in circulating tumour cells and cellular invasion. Clinical data from TCGA and breast cancer tissue microarrays revealed that NRG4 levels are significantly lower in tumour tissues compared with adjacent healthy tissues, and that higher expression levels correlate with improved patient survival outcomes. Mechanistically, the study highlights a pivotal regulatory role for the NRG4–ERBB4 signalling axis; NRG4 exerts its effects through binding to and activating the receptor tyrosine kinase ERBB4, leading to the generation of a cleaved intracellular domain that interacts with phosphorylated YAP1, thereby inhibiting its nuclear translocation and preventing its association with TEAD transcription factors that drive pro-metastatic gene expression programmes. In the absence of NRG4 signalling, active YAP1 translocates into the nucleus and binds to the transcription factor TEAD1, subsequently activating the transcription of matrix metalloproteinases, specifically MMP9 and MMP12, which facilitate extracellular matrix degradation and enhance tumour invasiveness. Conversely, NRG4-mediated inhibition of YAP1 activity results in their downregulation, effectively impairing the cellular machinery required for metastasis. Results from transcriptomic analyses, promoter activity assays, and protein interaction studies further confirm that the ERBB4–YAP1–TEAD axis serves as a central regulatory pathway controlling MMP expression and metastatic competence, while pharmacological or genetic inhibition of MMPs recapitulates the anti-metastatic effects observed with NRG4, reinforcing the functional importance of this signalling cascade. Experimental validation using recombinant NRG4 (rNRG4) and patient-derived breast cancer organoids revealed that rNRG4 inhibits lung metastasis, angiogenesis, and migration, underscoring how metabolic dysfunction in adipose tissue facilitates tumour progression by diminishing the protective effects of NRG4. Although the study demonstrates that NRG4 suppresses breast cancer metastasis via ERBB4–YAP1 signalling, the authors acknowledge that further investigation is needed to clarify the precise molecular interactions and post-translational modifications within this pathway, and to validate its prognostic and therapeutic potential through larger clinical cohorts and preclinical studies. In conclusion, this study shows that NRG4, by inhibiting the ERBB4–YAP1–MMP signalling cascade, suppresses breast cancer metastasis, thereby highlighting the therapeutic potential of targeting the NRG4–ERBB4 axis in metastatic breast cancer, particularly in obesity-associated disease contexts.