Ginsenoside Rg1 Counteracts the Negative Effects of a High‐Sugar Diet on Female Drosophila melanogaster Reproduction by Modulating Insulin and Steroid Hormone Signaling

The consumption of high‐sugar diets by women of reproductive age can adversely affect reproductive health by inducing hormonal and metabolic imbalance. This study investigated the efficacy of a natural compound, ginsenoside Rg1, in mitigating these negative phenotypes. It was found that prolonged high‐sugar intake led to obesity, lipid accumulation, ovarian atrophy, and reproductive disorders in female fruit flies. Treatment with ginsenoside Rg1 significantly alleviated the reproductive damage caused by the high‐sugar diet, including observed increases of 59.49% in egg production, 84.48% in pupariation numbers, and 19.68% in pupation success. Ginsenoside Rg1 also prevented sugar/fat accumulation, stabilized insulin levels, elevated the concentrations of 20‐hydroxyecdysone (20E), and restored endocrine balance. Mechanistically, Rg1 exhibited cellular target engagement with the insulin receptor (INR), leading to enhanced expression of its downstream extracellular signal‐regulated kinase (ERK) and estrogen receptor (ER) and increased insulin signaling. Rg1 also showed cellular target engagement with the steroid hormone receptor (ecdysone receptor [ECR]), boosting ecdysone‐induced protein 75B (Eip75B) and broad (Br) expression to activate steroid hormone signaling. These pathways acted synergistically to modulate expression of the yolk protein receptor and vitellogenin, critical for oogenesis. Molecular docking simulations predicted that Rg1 could interact with INR and ECR, a prediction corroborated by CETSA data indicating cellular target engagement. These findings collectively support a mechanistic model in which Rg1 physically engages both receptors to modulate downstream signaling. Alterations in gene expression in INR‐ and ECR‐mutant flies confirmed the mutual influence of insulin and steroid hormone signaling. Ginsenoside Rg1 may thus activate both insulin‐ and steroid hormone‐related signaling pathways to alleviate reproductive damage caused by high‐sugar diets. Furthermore, the activation of steroid hormone signaling by Rg1 was dependent on the presence of insulin signals. These findings provide preliminary mechanistic insights and generate testable hypotheses for future investigation into the potential of Rg1 in addressing reproductive disorders associated with long‐term excessive sugar intake.