Prolactin receptor signaling in liver homeostasis and disease

Prolactin (PRL) is a pleiotropic hormone that regulates diverse physiological processes beyond lactation through activation of the prolactin receptor (PRLR). The liver expresses high levels of PRLR and represents an important target organ for PRL signaling. However, the biological functions of hepatic PRLR, particularly those mediated by its multiple receptor isoforms, remain incompletely understood. In this review, we summarize current evidence regarding PRL/PRLR signaling in liver homeostasis and disease, with a focus on studies in rodents and humans. We first discuss the molecular diversity of PRLR isoforms and their distinct signaling properties, highlighting the predominance of short PRLR isoforms in both mouse and human liver. We then examine cell type-specific functions of PRLR signaling, PRL/growth hormone signaling crosstalk, and the role of PRLR signaling in modulating sexually dimorphic hepatic gene expression in homeostatic livers. Moreover, we summarized the current progresses in understanding how PRLR signaling is involved in various liver diseases, including liver fibrosis, liver cancer, and metabolic dysfunction-associated steatotic liver disease. Finally, we review pharmacological approaches targeting the PRL/PRLR axis for potential clinical development of treating liver diseases. Collectively, the available evidence identifies the PRL/PRLR axis as an important and highly context-dependent regulator of liver physiology and pathology. A better understanding of PRLR isoform-specific and cell type-specific signaling will be essential for determining whether PRLR-directed therapies can be safely and effectively translated into clinical applications for liver diseases.