Abstract

Background Non-small cell lung cancer (NSCLC) remains a prevalent and malignant cancer globally, characterized by chemotherapy resistance. The aim of this study was focused on the potential of ginsenoside (Gn)-Rh2 from ginseng exosomes (Gn-Exos), a primary bioactive constituent of Panax ginseng , to enhance chemotherapy sensitivity in NSCLC. Methods In this study, Gn-Exo was isolated and identified. The intake and internal organ distribution of PKH26-labelled Gn-Exos was detected using immunofluorescence and in vivo imaging. Transwell migration, 5-ethynyl-2′-deoxyuridine (EdU) incorporation, cell counting, and wound healing experiments were performed to assess NSCLC cell proliferation and migration. A mouse tumor xenograft model was constructed to assess the roles of Gn-Exos and the main active ingredient Gn-Rh2 in NSCLC progression and metastasis in vivo. Results Gn-Exos can inhibit the proliferation, migration, cancer growth, and pulmonary metastasis of NSCLC cells. Mass spectrometry analysis confirmed that the main component of Gn-Exos was Gn-Rh2. The results also showed that Gn-Rh2 inhibited the proliferation and migration of NSCLC cells in both in vivo and in vitro experiments. Comprehensive proteomic analysis identified ribonucleotide reductase regulatory subunit M2 (RRM2) and ubiquitin-specific protease 22 (USP22) as key targets significantly downregulated by Gn-Rh2. Experimental results demonstrated that Gn-Rh2 disrupts the interaction to USP22, disrupting the interaction between USP22 and RRM2, leading to ubiquitination degradation of RRM2. Animal experiments further confirmed that Gn-Rh2 sensitized NSCLC cells to chemotherapy, particularly cisplatin. Conclusion These findings provide novel insights into the molecular mechanisms of Gn-Rh2 in enhancing chemotherapy sensitivity and suggest a promising therapeutic strategy for NSCLC.