Jiao-tai-wan suppresses ferroptosis induced by heart-kidney disharmony insomnia by regulating the PDE4D/BDNF signaling pathway

Background Jiao-tai-wan (JTW) is a classic formula for Heart-Kidney Disharmony insomnia, yet its mechanism in hippocampal neurons remains unclear. Purpose To investigate whether JTW ameliorates insomnia-induced hippocampal neuronal damage by inhibiting ferroptosis and elucidate the underlying mechanisms. Methods UPLC-Q-TOF/MS analyzed JTW constituents. Network pharmacology and molecular docking predicted core targets. A mouse insomnia model was established using PCPA combined with MMPM. Behavioral tests, pathological examinations, and ferroptosis markers were evaluated. In vitro, HT22 cells underwent IKE-induced ferroptosis to validate Jiao-tai-wan drug-containing serum (JTWS) and the PDE4D inhibitor Zatolmilast (ZAT). Results 413 compounds were identified in JTW, with 47 predicted to penetrate the blood-brain barrier. Network pharmacology, molecular docking, and molecular dynamics simulations predicted PDE4D and BDNF as core targets. In vivo, JTW ameliorated cognitive deficits, attenuated hippocampal neuronal damage, and restored mitochondrial ultrastructure. Mechanistically, JTW downregulated Ptgs2 expression, upregulated Gpx4, Fth1, and Acsl3 expression, reduced lipid peroxidation and iron accumulation, while simultaneously suppressing Pde4d and restoring Bdnf levels. In vitro, ZAT mimicked the anti-ferroptotic effects of JTW. Conclusion JTW inhibits hippocampal neuronal ferroptosis through multi-target regulation, ameliorating insomnia-related neuronal damage and providing a molecular basis for its traditional efficacy in restoring Heart-Kidney communication. Download: Download high-res image (282KB) Download: Download full-size image