Recent advances in therapeutic signaling pathways in polycystic kidney disease: insights from contemporary translational disease models- a narrative review

Polycystic kidney disease (PKD) has undergone a major conceptual reappraisal over the past decade. Although PKD is fundamentally a monogenic disorder caused by mutations in PKD1, PKD2, PKHD1 , and related genes, it is now increasingly recognized that disease progression is regulated by complex and interconnected signaling networks arising from coordinated dysregulation across multiple regulatory pathways. Advances in experimental models, multi-omics technologies, and cross-species approaches have revealed that cyst initiation and progression arise from convergent defects in mechanosensation, epithelial proliferation, metabolic reprogramming, innate immune activation, and fibrotic remodeling. In this Review, we synthesize insights from genetically engineered mouse models, naturally occurring rodent strains, CRISPR/Cas9-based large-animal systems, and human cell–derived spheroids and induced pluripotent stem cell (iPSC)–derived kidney organoids. We highlight how conditional knockout platforms define the spatial and temporal origins of cystogenesis, whereas hypomorphic and allele-specific models clarify mutation- and dosage-dependent determinants of disease severity. These complementary systems connect upstream polycystin dysfunction to downstream therapeutic hubs, including vasopressin–cyclic AMP signaling, mTOR and AMPK pathways, Hippo–YAP/TAZ mechanotransduction, the cGAS–STING inflammatory axis, microRNA regulatory networks, and the gut–kidney axis. We further discuss how pathway-informed testing across model systems has accelerated the development of mechanism-based interventions, including vasopressin V2 receptor antagonists, nucleic acid–based microRNA therapeutics, metabolic modulators, kidney-targeted drug-delivery strategies, and rational combination therapies. Finally, we outline emerging directions for network-informed and stage-specific treatment strategies, emphasizing lineage-resolved targeting and translational validation in large-animal and human-derived platforms. This integrated framework provides a foundation for future therapies aimed at modifying the natural history of PKD. Clinical trial number Not applicable.