Aroyl diheterocyclic pyrrole (ARDHEP)@PLGA nanoparticles suppress human gastric cancer growth by modulating chromatin accessibility to activate the ZNF320-mediated cytokine-cytokine receptor pathway

Abstract Gastric cancer remains a significant global health threat, with mortality largely driven by drug resistance and peritoneal metastasis. Aroyl diheterocyclic pyrroles (ARDHEPs) are potent inhibitors of microtubule assembly but suffer from poor water solubility and limited bioavailability, restricting their therapeutic application. In this study, we developed poly(lactic-co-glycolic acid) (PLGA) nanoparticles loaded with ARDHEP (ARDHEP@PLGA) to overcome these pharmacological barriers. Our results, derived from both patient-derived human gastric cancer organoids and in vivo xenograft models, demonstrate that ARDHEP@PLGA significantly suppresses tumor growth, induces G0/G1 phase cell cycle arrest, and downregulates mitochondrial function. High-throughput ATAC-seq revealed that ARDHEP@PLGA markedly alters the landscape of chromatin accessibility within gastric cancer cells. Specifically, the treatment promotes the transcriptional activation of the transcription factor zinc finger protein 320 (ZNF320), as evidenced by increased trimethylated H3 lysine 4 (H3K4me3) binding at its promoter region. This epigenetic reprogramming subsequently triggers the activation of the cytokine–cytokine receptor interaction signaling pathway, leading to the significant upregulation of key inflammatory and tumor-suppressive molecules, including IFNAR2, LTA, and IL9, at both the mRNA and protein levels. These findings indicate that ARDHEP@PLGA nanoparticles exert their therapeutic effects by modulating chromatin accessibility to activate the ZNF320-mediated cytokine pathway. This study provides a novel nanotherapeutic strategy for gastric cancer treatment and highlights a specific epigenetic target for future intervention. Graphical Abstract