Intermittent fasting synergizes with GCN5 inhibition to suppress RBM5-AS1/GCN5/PGC-1α-driven Warburg metabolism in ovarian cancer.

Ovarian cancer is associated with high mortality largely due to late clinical detection, recurrent disease, and profound metabolic adaptations that support tumor survival. A major metabolic feature of ovarian tumors is a shift toward aerobic glycolysis. Recent evidence indicates that long non-coding RNAs contribute to this process by regulating epigenetic enzymes and metabolic pathways. The lncRNA RBM5-AS1 has been linked to activation of the acetyltransferase GCN5, resulting in functional suppression of PGC-1α, a key regulator of oxidative metabolism. Intermittent fasting has emerged as a metabolic strategy capable of disrupting tumor-specific metabolic dependencies; however, it's in vivo impact on the RBM5-AS1/GCN5/PGC-1α axis remains unclear. A VCH-induced ovarian cancer model in Wistar rats was employed to examine the effects of intermittent fasting alone or combined with pharmacological inhibition of GCN5 using MB-3. Tumor-bearing animals demonstrated severe physiological impairment, increased tumor burden, altered hematological and hepatic indices, hyperglycaemia, and heightened glycolytic activity, accompanied by elevated RBM5-AS1, GCN5, PDKs, GLUTs, and LDH expression, along with reduced PGC-1α and PDH levels. Intermittent fasting partially reversed these alterations by downregulating the RBM5-AS1/GCN5 axis and restoring oxidative metabolic signaling. Notably, fasting combined with MB-3 produced the most pronounced effects, resulting in substantial tumor regression, normalization of metabolic and biochemical parameters, recovery of ovarian tissue architecture, and effective suppression of glycolytic reprogramming. Collectively, these findings identify Targeting the RBM5-AS1/GCN5/PGC-1α axis through combined metabolic and epigenetic intervention effectively restrains ovarian tumor progression and represents a promising low-toxicity therapeutic strategy.