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Mechanism of Huaiqihuang (HQH) against cyclophosphamide (CYP)-induced hippocampal neurotoxicity based on network pharmacology; molecular docking and experimental verification
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DOI：10.3389/fcell.2025.1629110.png)
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Abstract
En 中文
BackgroundCyclophosphamide (CYP) is widely used for the treatment of cancer and autoimmune diseases. However; neurotoxicity accompanied with application of CYP seriously affects the final clinical outcome. Huaiqihuang (HQH) is a Chinese herbal complex with immunomodulatory effect and widely used for treating various diseases. The present research was conducted to evaluate the protective effect of HQH against CYP-induced neurotoxicity and to elucidate the underlying mechanisms.MethodsSprague–Dawley rats were randomly divided into four groups (10 per group): the CYP-only group (single dose of 200 mg/kg); low- and high-dose HQH + CYP groups (pretreatment with 3 or 6 g/kg HQH for 5 days); and control (saline) group. Histopathological analysis and behavioral tests was used to evaluate the therapeutic effects of HQH on CYP-induced neurotoxicity. Network pharmacology; molecular docking; and Western blot were employed to assess the anti-neurotoxicity mechanisms.ResultsBoth doses of HQH restored histopathological aberrations; oxidative stress and inflammation caused by CYP in rats. Behavioral tests showed that HQH pretreatment improved motor coordination and balance in CYP-treated rats. Network pharmacology identified core targets including HSP90AA1; TP53; MAPK1; AKT1; RELA; TNF. Molecular docking revealed that TNF; HSP90AA1; TP53; and MAPK1 had strong binding affinities with CYP. Experimental validation using Western blot confirmed that HQH significantly decreased the protein expression of TNF; HSP90AA1; TP53; and MAPK1 in hippocampal tissues.ConclusionHQH mitigates CYP-induced hippocampal neurotoxicity by decreasing oxidative stress; and inflammation; with HSP90AA1 being a key target; providing a novel therapeutic strategy for chemotherapy-associated cognitive impairment.
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