Sijunzi Decoction Reverses Metabolic Adaptation and Induces Ferroptosis in Cisplatin-Resistant Non–small Cell Lung Cancer: An Integrative Metabolomics–Pharmacology Analysis

OBJECTIVE: To investigate the mechanistic role of Sijunzi decoction (SJZD) in overcoming chemoresistance through the suppression of adaptive metabolic responses in non-small cell lung cancer (NSCLC). METHODS: probe for lipid peroxidation. siRNA-mediated gene silencing and immunohistochemical analysis were performed to elucidate the functional hierarchy of the p62/Keap1/nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant axis. Complementary in vivo validation was performed using BALB/c nude mice bearing A549/DDP xenografts, with longitudinal monitoring of tumor progression under SJZD treatment regimens. RESULTS: Untargeted metabolomics of SJZD-medicated serum revealed 392 differentially abundant metabolites, with pathway enrichment revealing significant dysregulation of glutamine metabolism. Structural validation confirmed 55 bioactive components of SJZD in serum, including glycyrrhizin, ginsenoside Ro, liquiritigenin, and atractylenolide I. Integration of these components with disease targets yielded 355 overlapping genes associated with both SJZD activity and cisplatin-resistant NSCLC, with significant enrichment in oxidative stress response pathways. Experimental assays confirmed that SJZD induced ferroptosis in cisplatin-resistant A549/DDP cells, as evidenced by disrupted iron homeostasis, lipid peroxidation, and characteristic mitochondrial damage. These effects and subsequent cell death were specifically abrogated by the ferroptosis inhibitor ferrostatin-1 (Fer-1) but not by apoptosis inhibition, confirming that ferroptosis is the primary mechanism of cell death. Mechanistically, the inhibition of p62/Keap1/Nrf2 signaling was involved in the modulation of SJZD-induced ferroptosis both in vitro and in vivo. CONCLUSIONS: SJZD counteracts metabolic adaptation through ferroptosis mediated by the inhibition of p62/Keap1/Nrf2 in cisplatin-resistant NSCLC.