Pinocembrin in Indian lychee honey destabilizes hepatic lncRNA NEAT1 by inhibiting ALKBH5-mediated m6A-demethylation in non-alcoholic fatty liver disease condition

Non-alcoholic fatty liver disease (NAFLD) is a growing global health concern linked to metabolic dysfunction. Long non-coding RNAs (lncRNAs) like NEAT1 play critical roles in NAFLD pathogenesis. This study investigates the therapeutic potential of Indian lychee honey (LyH) and pinocembrin, a major component of LyH, against NAFLD. Mechanistically, the data showed that pinocembrin destabilized NEAT1 by inhibiting the activity of ALKBH5, a m6A RNA demethylase. RNA immunoprecipitation and RNA stability assay with actinomycin D further confirmed that this inhibition decreased the m6A modification of NEAT1, leading to its degradation. Furthermore, the effects of pinocembrin and LyH treatment against NEAT1 stabilization and lipid accumulation were validated by using a pharmacological inhibitor of ALKBH5 (cpd 20 m). These findings demonstrate that pinocembrin, a predominant phytochemical present in LyH, reduces lncRNA NEAT1 expression, correlating with attenuated lipid accumulation. Future studies employing NEAT1 gain-of-function would better clarify the mechanistic causality for this effect. Overall, this study offers LyH as a promising therapeutic strategy for NAFLD management by targeting the ALKBH5/NEAT1 axis. Graphical abstract: Mechanism of pinocembrin present in Indian lychee honey (LyH) to reduce hepatic liptd accumulation by destabilizing lncRNA NEAT1 in NAFLD condition. • Indian lychee honey (LyH) reduces hepatic lipid accumulation by destabilizing lncRNA NEAT1 in palmitic acid-treated conditions. • Pinocembrin efficiently binds to ALKBH5 (RNA demethylase) to inhibit NEAT1 m6A demethylation and stabilization. • Pinocembrin and cpd 20 m (a pharmacological inhibitor of ALKBH5) bind to the active site of ALKBH5. • Cpd 20 m efficiently reduces hepatic lipid accumulation in palmitic acid-treated cells.