The chemical composition of the ethanol extract of Acanthopanax senticosus fruit (ASFEE) was systematically characterized using UPLC-MS/MS (Q Exactive Orbitrap), leading to the identification of 45 compounds. Through integrated network pharmacology and molecular docking analyses, the binding affinities between key bioactive constituents—such as eleutheroside E (EE) and quercetin—and core therapeutic targets were predicted and validated. A total of 125 overlapping targets were identified between ASFEE and acute kidney injury (AKI), with significant enrichment observed in critical signaling pathways, including NF-κB, IL-17, and PI3K-Akt. To evaluate the protective effects of ASFEE, both in vitro (HK-2 cells) and in vivo (murine) models of cisplatin (DDP)-induced AKI were employed. Parameters assessed included cell viability, apoptosis, reactive oxygen species (ROS) production, activation of the NF-κB signaling pathway, kidney function, histopathological alterations, and levels of inflammatory cytokines. ASFEE treatment markedly enhanced HK-2 cell viability and reduced cellular apoptosis and ROS generation. In the murine model, DDP administration resulted in significantly elevated serum creatinine (Scr) and blood urea nitrogen (BUN) levels. Both low- and high-dose ASFEE treatments significantly attenuated these increases, improved overall kidney function, and alleviated kidney tubular damage. Furthermore, ASFEE reduced serum levels of pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α. Multi-omics integration analysis enabled the identification of differentially expressed genes and metabolites. ASFEE was found to reverse 4689 DDP-induced gene expression changes and 323 metabolic disturbances, with the uridine diphosphate glucuronosyltransferase (UGT)-mediated ascorbic acid metabolism pathway emerging as the central regulatory axis. Key candidate genes and proteins were further validated via real-time quantitative polymerase chain reaction (RT-qPCR) and Western blotting. DDP significantly upregulated the expression of inflammatory markers and associated signaling molecules in kidney tissues, while concurrently downregulating UGT family genes and the UGT1A1 protein involved in uronic acid metabolism. Notably, ASFEE treatment effectively counteracted these alterations, confirming its role in enhancing UGT1A1-mediated metabolic processes and suppressing the NF-κB/PI3K-Akt/IL-17 signaling cascade. These mechanisms contribute to improved antioxidant capacity, mitigation of inflammatory responses, and restoration of metabolic homeostasis, thereby conferring protection against DDP-induced AKI. ASFEE exerts a protective effect on AKI caused by DDP by enhancing antioxidant capacity, inhibiting inflammation and restoring metabolic homeostasis, providing an experimental basis for its subsequent development and application.

Targeting the crosstalk between histone methyltransferases G9a and EZH2 represents a promising strategy for cancer therapy. To improve upon our previously reported dual inhibitor SU08, we rationally designed and synthesized five series (SU, UA, UB, N, and L) of novel G9a/EZH2 dual inhibitors, incorporating diverse pyridone, urea, and thienopyrimidine moieties, yielding a total of 43 compounds. In vitro enzymatic screening revealed that compound SU101 against both EZH2 (IC₅₀ = 4.08 nM) and G9a (IC₅₀ = 2.92 nM) was comparable to SU08. Western blot analysis confirmed that SU101 and SU103 effectively suppressed both H3K27me3 and H3K9me2 expression in rhabdomyosarcoma RD cells. In cellular antiproliferative assays, SU101 showed the strongest activity (IC₅₀ = 15.33 μM). Molecular docking and dynamics simulations verified stable binding interactions between SU101 and both target proteins. Pharmacokinetic studies in rats demonstrated that SU101 possesses excellent oral bioavailability (94.3%), moderate plasma protein binding (84.6%), and an acceptable acute toxicity profile (LD₅₀ = 31.02 mg/kg in mice). Overall, these results suggest that SU101 may serve as a promising lead compound for further optimization and support the continued exploration of dual G9a/EZH2 inhibitors as a potential therapeutic approach for rhabdomyosarcoma.