GPER1: A Hidden Key in Cardio-Renal Axis-Unveiling its Therapeutic Potential for Heart and Kidney Disease.

Cardiovascular and kidney diseases are tightly interconnected through a bidirectional cardio-renal axis and exhibit pronounced sex-specific differences, implicating estrogen-associated signaling networks as critical modulators of disease susceptibility and progression. Among these, G protein-coupled estrogen receptor 1 (GPER1,GPR30) has emerged as a rapid signaling hub integrating vascular function, inflammatory responses, oxidative stress, and tissue remodeling across the cardiac, renal, and vascular tissues. However, interpretation of the extensive phenotype literature-largely derived from studies using the prototypical agonist G-1-has become increasingly complex in light of recent advances in receptor structural biology and evolving physiological models. Accumulating evidence indicates that GPER1-associated signaling can attenuate maladaptive cardiac remodeling and inflammatory injury, modulate renal tubular transport and redox homeostasis, and preserve endothelial integrity through coordinated regulation of nitric oxide and endothelin pathways. Across organ systems, these effects converge on shared downstream signaling modules, including TGF-β/Smad, PI3K/Akt/eNOS, and NF-κB pathways. At the same time, emerging structural data, including identification of structurally supported agonists and alternative physiological activation mechanisms, challenge assumptions regarding direct ligand-receptor engagement. In this context, translational progress will require a more rigorous framework that integrates structure-guided pharmacology, standardized validation linking ligand binding to downstream signaling in matched experimental systems, and genetic epistasis approaches combining loss-of-function and rescue strategies. Rigorous mechanistic validation is essential to establish causal GPER1-associated signaling across the cardio-renal axis. Such approaches are required to determine whether GPER1 represents a tractable therapeutic target in combined cardiac and kidney disease.