Combined Lingzhi Huang capsules and Zeng Jian health tonic accelerates skin wound healing via BMP5-mediated inhibition of ferroptosis.

Introduction: Lingzhi Huang capsules (LZH) and Zeng Jian Health Tonic (ZJ) are traditional Chinese medicinal formulations enriched in polysaccharides and antioxidant components. They have been traditionally used to enhance immunity function and reduce inflammation, promote tissue repair. However, their therapeutic efficacy and underlying mechanisms in skin wound healing have not been fully elucidated. Guided by the Traditional Chinese Medicine principle of "treating the same disease with different therapeutic strategies," this study aimed to evaluate the effects of LZH and ZJ, administered individually and in combination, on skin wound healing and to elucidate the associated molecular mechanisms. Methods: The chemical constituents of LZH and ZJ were characterized using liquid chromatography-tandem mass spectrometry (LC-MS/MS). A full-thickness skin wound model in mice was employed to assess therapeutic effects through histopathological analysis, immunofluorescence, Western blotting, and protein antibody array analysis. In vitro, human umbilical vein endothelial cells (HUVECs) were used to investigate angiogenesis, inflammation, oxidative stress, and ferroptosis. Network pharmacology integrated with protein array profiling was applied to identify key targets and signaling pathways involved in the combined treatment, which were subsequently validated through mechanistic experiments. Results: LZH and ZJ significantly accelerated wound closure, enhanced collagen deposition, and promoted angiogenesis, with the combined treatment exhibiting the most pronounced effects. In HUVECs, LZH + ZJ markedly enhanced cell proliferation, migration, and tube formation; increased CD31 and VEGF expression; reduced reactive oxygen species (ROS) levels; elevated SOD and GSH; decreased MDA levels, and alleviated mitochondrial damage. These effects were accompanied by upregulation of GPX4, SLC7A11, and FTH1. Integrated network pharmacology and protein array analyses revealed enrichment of pathways associated with angiogenesis, inflammation, and ferroptosis, and identified BMP5 as a central regulatory target. Mechanistic validation demonstrated that BMP5 overexpression recapitulated the anti-ferroptotic effects of LZH + ZJ, whereas BMP5 knockdown abolished these protective effects. Conclusion: Combined administration of LZH and ZJ promotes skin wound healing more effectively than either treatment alone by suppressing ferroptosis, inflammation, and oxidative stress through BMP5-mediated signaling. These findings provide mechanistic support for the traditional therapeutic rational and suggest a promising strategy for enhancing wound healing.