Kaixuan Jiedu Decoction alleviates imiquimod-induced psoriasis-like skin lesions by inhibiting oxidative stress and enhancing mitochondrial homeostasis through the PI3K/AKT/mTOR pathway.

AIM OF THE STUDY: Kaixuan Jiedu Decoction (KXJD) is a compound herbal formula rooted in the classical "Xuanfu theory" of Traditional Chinese Medicine and has long been clinically used for psoriasis management, yet the cellular and molecular mechanisms remain incompletely understood. The study aims to explore the effects of KXJD on psoriasis-like inflammation, with a focus on oxidative stress, mitochondrial homeostasis, and the potential involvement of PI3K/AKT/mTOR signaling. METHODS: The effects of KXJD were evaluated in imiquimod (IMQ)-induced psoriasis-like mouse model and M5 cytokine-stimulated HaCaT keratinocytes. Candidate targets and signaling pathways were prioritized using network pharmacology and molecular docking. Rescue experiments with the PI3K activator 740YP, performed both in vivo and in vitro, were used to investigate the involvement of the PI3K/AKT/mTOR pathway. RESULTS: KXJD ameliorated IMQ-induced psoriasis-like skin lesions, decreasing epidermal hyperplasia, keratinocyte proliferation, and systemic inflammation. KXJD reduced oxidative stress, as reflected by lower ROS and MDA and higher GSH, CAT, and ATP, and it restored mitochondrial integrity by rebalancing mitochondrial dynamics and normalizing elevated mitophagy-associated markers. Network pharmacology and molecular docking nominated PI3K/AKT/mTOR pathway as the leading candidate regulatory pathway, with Palbinone and Polydatin showing the highest predicted binding affinities for PI3K, AKT1, and mTOR among the blood-absorbed components. Activation of PI3K by 740YP partially reversed the protective effects of KXJD on skin lesions, oxidative stress, and mitochondrial alterations in both models. CONCLUSIONS: KXJD alleviates psoriasis-like skin lesions in association with reduced PI3K/AKT/mTOR signaling, which in turn enhances mitochondrial quality control and diminishes oxidative stress in keratinocytes.