Licoisoflavone A ameliorates adipose tissue dysfunction in diet‑induced obesity by promoting METTL3 expression

With the development of obese adipose tissue (AT), adipocytes undergo pathological changes from inert energy storage to excessive and active endocrine organs associated with disease hazards. Methyltransferase 3 (METTL3) is an RNA methyltransferase with key roles in AT development, functional maintenance and metabolic homeostasis. Licoisoflavone A (LIC‑A) is a prenylated flavonoid compound derived from licorice, which has anti‑inflammatory, antihypertrophic and antiproliferative activities; however, whether it directly modulates METTL3 expression and affects AT function in obesity remains unknown. In the present study, molecular docking of compounds from the traditional Chinese medicine formula Fangji‑Huangqi Decoction against METTL3, identified 16 top‑ranked candidate molecules. Among these candidates, LIC‑A was identified as a potential upstream regulator of METTL3 and markedly increased METTL3 expression. The effects of TNF‑α and lipopolysaccharide treatments on the inhibition of adipogenesis were successfully recovered by LIC‑A treatment of the adipogenic 3T3‑L1 cells, via the regulation of adipogenic cytokines, as well as the expression of inflammatory factors. These protective effects were similarly abolished by METTL3 knockdown, suggesting that the role of LIC‑A relies on METTL3. Moreover, in vivo data demonstrated that the administration of LIC‑A could notably recover body weight lipid metabolism, insulin resistance and gluconeogenesis in mice with reduced adipose deposition, as well as abate systemic inflammation. The novelty of the present study lies in three aspects: i) LIC‑A was identified as a previously unrecognized upstream positive regulator of METTL3 expression; ii) LIC‑A was demonstrated to alleviate adipokine dysregulation and AT inflammation through a METTL3‑dependent mechanism; and iii) the first in vivo experimental evidence that LIC‑A can improve obesity‑related metabolic disorders by promoting METTL3‑mediated m6A methylation in AT was provided. To the best of our knowledge, this is the first study to link a natural isoflavone compound from licorice to METTL3‑mediated post‑transcriptional regulation in the context of AT dysfunction.