Tanotnon Tanawattanasuntorn,^a,b Paradesi Naidu Gollavilli,^b Adriana Martinez Turtos,^b Mohammad Aarif Siddiqui,^b Vignesh Ramesh,^b Tienthong Thongpanchang,^c
Khotchawan Bangpanwimon,^a Adisak Noonai,^a Paolo Ceppi,^b,* Potchanapond Graidist^d,*

^aDepartment of Medical Technology, Faculty of Allied Health Sciences, Pathumthani University, Pathum Thani 12000, Thailand

^bDepartment of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, Odense 5230, Denmark

^cDepartment of Chemistry and Center of Excellence for Innovation in Chemistry (PERCH-CIC), Faculty of Science, Mahidol University, Bangkok 10400, Thailand 

^dDepartment of Biomedical Sciences and Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand

This study explored how trans-(±)-kusunokinin (KU) may help treat non-small cell lung cancer (NSCLC). KU is known to block AKR1B1, an enzyme involved in the polyol pathway, which converts glucose into other sugars. This pathway can increase oxidative stress and disrupt cell metabolism, both of which help cancer grow and spread. High levels of AKR1B1 are linked to worse outcomes in lung cancer patients. KU was tested in lung cancer cells grown in the laboratory and in mouse models. KU slowed cancer cell growth and reduced the ability of cancer cells to migrate, even under high-glucose conditions. KU also lowered the levels of AKR1B1 and related enzymes, reduced harmful sugar buildup inside cells, and changed proteins that control how cancer cells spread. Notably, KU showed these effects at lower doses than epalrestat, a known AKR1B1 inhibitor. In mice with aggressive lung tumors, KU significantly extended survival. Overall, the findings suggest that KU may reduce lung cancer aggressiveness by targeting cancer metabolism and cell movement, supporting further investigation in clinical studies.