by Ying-Jun Dong, Kun Xi, Ya-Zhi Zhang, Jian-Heng Xue, Dan-Dan Shen, Shao-Kun Zang, Ruozhu Zhao, Hai Qi, Chunyou Mao, Wei-Wei Wang, Yan Zhang G protein-coupled receptor 174 (GPR174), a key modulator of autoimmune responses, maintains immune homeostasis through distinct G protein signaling pathways, particularly G s and G i . Although the structural mechanism of lysophosphatidylserine (LysoPS)-activated GPR174 in the G s pathway has been characterized, how hydration-mediated interactions influence GPR174 activation and signaling selectivity remains unclear. Here, we determined high-resolution cryo-electron microscopy (cryo-EM) structures of LysoPS-activated human GPR174 bound to G s (2.0 Å) and G i (3.4 Å), revealing a continuous hydration-mediated signal transduction network that bridges the sodium-binding pocket, the NPxxY and DRY motifs, and the G protein-binding interface. This network stabilizes the active-state conformation of GPR174 and dynamically reshapes the intracellular cavi