Fresh Ginseng Reduces Sphingosine Secretion Through Ubiquitin Degradation of SPTLC2 to Antagonize the Progression of Non‐Small Cell Lung Cancer

ABSTRACT Non‐small cell lung cancer (NSCLC) remains the leading cause of cancer‐related mortality, with current therapies limited by toxicity and resistance. Fresh Panax ginseng C. A. Mey homogenate extract (FG) retains intact bioactive constituents through nonthermal processing, thereby preserving its native pharmacological integrity. The aim of this study was to systematically investigate the therapeutic effects of FG on nonsmall cell lung cancer and elucidate its mechanism of targeting sphingolipid metabolism. LLC tumor‐bearing C57BL/6J mice were used to evaluate the inhibitory effect of FG on tumors. In vitro experiments were conducted using A549 and H1975 cells as models to analyze the effects of FG‐containing serum on proliferation and cell cycle through EdU, clone formation, and flow cytometry. The combination of metabolomics (UHPLC Orbitrap MS) and proteomics (DIA‐MS) was used to screen differential metabolites and proteins. Western blot and RT‐qPCR were used to verify its mechanism, Co‐IP was used to detect SPTLC2 ubiquitination levels, and MG132 inhibition experiments were conducted to clarify the ubiquitin proteasome system (UPS) dependence and deepen the mechanism research. FG exerted antitumor activity both in vitro and in vivo. Notably, SPTLC2 silencing not only phenocopied FG's effects but also diminished FG‐mediated tumor suppression, while exogenous sphingosine reversed its therapeutic efficacy in vitro. Mechanistically, FG targeted the ubiquitin‐proteasome system to degrade SPTLC2, thereby reducing sphingosine secretion, as evidenced by attenuated serum sphingosine levels in SPTLC2‐deficient tumors. This study provides evidence that FG inhibits the progression of nonsmall cell lung cancer by targeting the SPTLC2‐sphingosine axis, demonstrating its ability to specifically regulate sphingolipid metabolism with low toxicity. These findings support the potential of FG as a promising candidate therapeutic agent for nonsmall cell lung cancer.