Targeting the polyol pathway in NSCLC: Trans-(±)-kusunokinin demonstrates anti-migratory and survival benefits in in vitro and in vivo models

Trans-(±)-kusunokinin (KU), a potential anticancer agent, has been reported as an AKR1B1 inhibitor, a key enzyme in the polyol pathway that converts glucose to sorbitol and subsequently to fructose via sorbitol dehydrogenase (SORD). This pathway contributes to oxidative stress and metabolic dysregulation which promote cancer progression and metastasis. Overexpression of AKR1B1 is associated with a poor prognosis in non-small cell lung cancer (NSCLC). This study aimed to elucidate the anticancer mechanism of KU in NSCLC. KU inhibited proliferation in a dose-dependent manner in human A549 cells and in mouse lung cancer cell lines derived from AAV-CRISPR/Cas9-induced KRAS^G12DP53^-/- (KP) and KRAS^G12DP53^-/-LKB1^-/- (KPL) models. KU also significantly reduced cell migration in a dose-dependent manner under both normal and high glucose conditions. Remarkably, KU suppressed AKR1B1 and SORD expression, reduced intracellular sorbitol and fructose levels, and induced alterations in EMT-related proteins, such as ZEB1, E-cadherin, and vimentin, at a lower concentration than epalrestat (EP), a known AKR1B1 inhibitor. In vivo, KU significantly prolonged the survival of mice carrying KPL lung tumors compared to the control group. Collectively, these findings suggest that KU inhibits the aggressive phenotype of lung cancer by targeting the polyol pathway and modulating EMT processes. These results support its potential as a therapeutic candidate, highlighting the need for clinical evaluation in NSCLC patients.