Targeting Stearoyl-CoA Desaturase-1 (SCD1) by the Drug–Nutraceutical Combination of Montelukast and Bixin in Ameliorating Steatotic NAFLD

Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome, which progresses from simple fat accumulation (steatosis) to nonalcoholic steatohepatitis (NASH), fibrosis, and eventually liver cancer. Stearoyl-CoA desaturase 1 (SCD1), a key lipogenic enzyme, plays a significant role in the progression of NAFLD by promoting the accumulation of fat in the liver. This study investigated the drug-nutraceutical combination of Montelukast (a synthetic anti-inflammatory drug) and Bixin (an apo-carotenoid) as SCD1 inhibitors for treating fatty liver disease. Bixin was identified through virtual screening of a curated carotenoid database (carotenoid DB) targeting lipogenic enzyme SCD1. In the <i>in vitro</i> model of steatotic HepG2 cells, the combination treatment of Montelukast and Bixin showed a marked reduction (<i>P</i> < 0.05) in SCD1 gene expression (41%), protein expression (61%), and SCD1 enzyme activity (56.22%). The combination treatment showed a significant reduction of 21.64% (<i>P</i> < 0.05) in lipid accumulation relative to individual treatment with Bixin or Montelukast and was comparable with the reference drug Aramchol (21.83%). The markers of oxidative stress were also significantly reduced (<i>P</i> < 0.05), evidenced by decreased MDA (42.25%), RNS levels (32.59%), and ROS levels (30.72%) in the combination group. These findings suggest that Bixin and Montelukast in combination hold potential for managing the multiple aspects in the pathophysiology of NAFLD development and progression.