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Glucose 6-phosphate dehydrogenase (G6PD) is crucial for redox balance and biosynthesis via the pentose phosphate pathway (PPP), driving non-small cell lung cancer (NSCLC) proliferation. This study assessed the cytotoxic and enzymatic effects of five 1,2-naphthoquinone (NQ) derivatives, including SJ006 derived from Usnea barbata, in NSCLC cell lines (A549 and NCI-H292) compared to traditional inhibitors (DHEA and 6AN). All 1,2-NQs demonstrated concentration-dependent cytotoxicity against NSCLC cells. Among them, NN02 exhibited the highest cytotoxicity comparable to 6-AN, followed by NN01, NN04, SJ006, and SJ007, which showed moderate effects comparable to DHEA. SJ006 uniquely inhibited G6PD activity without altering its mRNA or protein expression. Unlike DHEA and 6AN, SJ006 functioned as an uncompetitive inhibitor, decreasing both K_m and V_max, with molecular docking confirming strong G6PD binding. Additionally, SJ006 increased reactive oxygen species (ROS) levels, induced G2/M cell cycle arrest, and triggered late apoptosis in NSCLC cells. Its effects were reversed by D-(-)-ribose, confirming PPP disruption as the mechanism. These results highlight SJ006 as a novel G6PD inhibitor that disrupts redox homeostasis and biosynthesis-driven cell proliferation, showing promise as an anticancer agent for NSCLC.