Zhuhuang granules inhibit HIF-1α signaling to regulate oxidative stress-mitochondrial function axis to improve psoriasis.

Psoriasis is a chronic immune-mediated skin disorder characterized by keratinocyte hyperproliferation and persistent inflammation. This study evaluated the therapeutic effects of Zhuhuang granules and investigated their underlying mechanism. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), network pharmacology, and molecular docking were combined with an imiquimod (IMQ)-induced psoriasis-like mouse model and a HaCaT cell model stimulated with an M5 cytokine cocktail (interleukin-17A, interleukin-22, oncostatin M, interleukin-1α, and tumor necrosis factor-α). UPLC-MS/MS identified multiple compounds and 174 absorbed prototype components. Network analysis prioritized the hypoxia-inducible factor 1 subunit alpha gene (HIF1A), while molecular docking predicted potential interactions of gardenoside and kaempferol with the encoded hypoxia-inducible factor-1α (HIF-1α) protein. In the psoriasis mouse model, Zhuhuang granules dose-dependently alleviated erythema, scaling, and epidermal thickening, with methotrexate serving as a positive control. Zhuhuang granules also reduced reactive oxygen species (ROS), malondialdehyde, interleukin-17A, and interleukin-23 levels, restored glutathione levels and superoxide dismutase and catalase activities, and preserved mitochondrial membrane potential. In M5-stimulated HaCaT cells, Zhuhuang granule-containing serum inhibited proliferation and inflammatory cytokine release, reduced mitochondrial ROS, lactate, and mitochondrial DNA release, and improved mitochondrial membrane potential. These effects were accompanied by reduced HIF-1α and tumor necrosis factor receptor 1 protein levels and phosphoinositide 3-kinase phosphorylation. Molidustat attenuated these protective effects. Collectively, Zhuhuang granules ameliorate psoriasis-like alterations by suppressing HIF-1α-associated oxidative stress, inflammation, and mitochondrial dysfunction.