Polyphyllin I Alleviates Alcoholic Liver Disease via Modulation of the Phosphodiesterase 6D –Cyclic Guanosine Monophosphate–Protein Kinase G Axis

Alcoholic liver disease (ALD) is a multifaceted disorder in which oxidative injury, iron-dependent ferroptosis, steatosis, and inflammation are closely intertwined. Consequently, therapeutic strategies targeting a single pathway often produce limited clinical benefits. In this study, we identified polyphyllin I (PPI), a bioactive constituent isolated from Paris polyphylla, as a potent hepatoprotective agent that concurrently ameliorates these pathological phenotypes in ethanol-exposed hepatocytes and a murine ALD model. Cellular thermal shift assay (CETSA) confirmed cellular engagement between PPI and PDE6D. Mechanistically, PPI regulates PDE6D to elevate intracellular cGMP levels and subsequently activate PKG signaling. Genetic perturbation experiments revealed that PDE6D exacerbates ethanol-induced hepatocyte ferroptosis via cGMP downregulation, and the hepatoprotective effects of PPI could be recapitulated by the PDE6D degrader TMX-4100. Downstream of PKG activation, PPI simultaneously restores xCT/GPX4 expression, suppresses ACSL4-mediated lipid peroxidation to inhibit ferroptosis, promotes NRF2 nuclear translocation to strengthen antioxidant defenses, restores autophagic flux to eliminate lipid droplets, and attenuates canonical NF-κB activation to alleviate hepatic and systemic inflammation. Pharmacological inhibition of PKG abrogated all four aforementioned effects, verifying pathway dependency. These findings establish PDE6D as a druggable vulnerability in ALD and suggest that PPI simultaneously suppresses ferroptosis and reprograms metabolic and immune homeostasis through the PDE6D-cGMP-PKG axis.