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Sulforaphane (SFN), a compound from cruciferous vegetables, mimics fasting by activating cellular starvation responses. This fasting-mimetic effect may explain SFN's therapeutic benefits and potential toxicity.

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Area of Science:

  • Biochemistry
  • Cell Biology
  • Nutritional Science

Background:

  • Sulforaphane (SFN) is a cruciferous vegetable-derived isothiocyanate with known anti-cancer, anti-microbial, and anti-oxidant properties.
  • SFN has shown efficacy in rodent disease models, similar to dietary restrictions, prompting investigation into its fasting-mimetic potential.

Purpose of the Study:

  • To investigate whether sulforaphane (SFN) elicits cellular responses consistent with fasting or caloric restriction.
  • To explore the impact of SFN on nutrient-sensing pathways in human retinal pigment epithelial cells.

Main Methods:

  • Treatment of immortalized human retinal pigment epithelial cells with SFN.
  • Analysis of mitochondrial mass, oxidative stress resistance, mTORC1/2 activity, insulin signaling, autophagy, lysosomal biogenesis, glucose uptake, and lactate secretion.
  • Measurement of thioredoxin-interacting protein (TXNIP) and pyruvate dehydrogenase phosphorylation.
  • Analysis of glycolytic and tricarboxylic acid (TCA) cycle intermediates.
  • RNA sequencing (RNA-seq) to identify transcriptional changes.

Main Results:

  • SFN increased mitochondrial mass and oxidative stress resistance.
  • SFN suppressed mTORC1/2 activity by inhibiting insulin signaling and upregulated autophagy and lysosomal biogenesis.
  • SFN acutely decreased glucose uptake and lactate secretion, with a rebound linked to suppressed TXNIP.
  • SFN altered metabolic intermediates and promoted pyruvate entry into the TCA cycle, indicative of starvation response.
  • RNA-seq confirmed activation of starvation-responsive transcriptional programs.

Conclusions:

  • SFN exhibits fasting-mimetic properties by impacting key nutrient-sensing pathways.
  • These fasting-mimetic effects may contribute to both the therapeutic efficacy and potential toxicity of sulforaphane.
  • SFN's influence on metabolic pathways suggests a role in cellular adaptation to nutrient deprivation.