Intermittent Fasting and GCN5 Inhibition Synergistically Suppress Ovarian Cancer Progression and Warburg Metabolism in Rats

Ovarian cancer is highly lethal due to late detection, recurrence, and profound metabolic adaptations, notably a shift towards aerobic glycolysis (Warburg effect). Current treatments often fail to address these metabolic dependencies effectively. The lncRNA RBM5-AS1 activates the acetyltransferase GCN5, which in turn suppresses PGC-1α, a crucial regulator of oxidative metabolism. While intermittent fasting shows promise in disrupting tumor metabolism, its specific in vivo effects on this RBM5-AS1/GCN5/PGC-1α axis in ovarian cancer remained unexplored.

Researchers utilized a VCH-induced ovarian cancer model in Wistar rats to investigate intermittent fasting (IF) alone or combined with pharmacological inhibition of GCN5 using MB-3. Tumor-bearing animals were compared to control groups. Primary endpoints included tumor burden, physiological and metabolic parameters, and expression levels of key metabolic and epigenetic regulators. Assays measured RBM5-AS1, GCN5, PDKs, GLUTs, LDH, PGC-1α, and PDH to assess glycolytic activity and oxidative metabolism.

Untreated tumor-bearing rats exhibited severe physiological impairment, increased tumor burden, altered hematological and hepatic indices, and hyperglycemia. This was accompanied by heightened glycolytic activity, marked by elevated expression of RBM5-AS1, GCN5, PDKs, GLUTs, and LDH, alongside reduced PGC-1α and PDH levels. Intermittent fasting partially reversed these detrimental alterations by downregulating the RBM5-AS1/GCN5 axis and restoring oxidative metabolic signaling.

Notably, the combination of intermittent fasting with MB-3 produced the most pronounced therapeutic effects, resulting in substantial tumor regression, normalization of metabolic and biochemical parameters, recovery of ovarian tissue architecture, and effective suppression of glycolytic reprogramming.