Natural compounds targeting glycolysis and TME in ovarian cancer: from metabolic crosstalk to therapeutic potential.

Ovarian cancer (OC) cells promote rapid proliferation via aerobic glycolysis and build an immunosuppressive microenvironment at the same time; therefore, this glycolytic pathway is now a potential drug target. Existing glycolysis inhibitors are limited by off-target toxicity, drug resistance, and variable efficacy across tumor subtypes. Natural compounds offer an alternative by modulating multiple glycolytic nodes, lowering lactate production, and reshaping the tumor microenvironment (TME). Therefore, this review summarizes 33 natural compounds that target glycolysis in OC. Their mechanisms of action focus on inhibiting glucose uptake, downregulating the PI3K/AKT/mTOR signaling pathway, suppressing the activities of glycolytic enzymes (HK2, PFK, PKM2, and LDHA) and HIF-1α transcription, reducing lactate production, ameliorating the TME, and ultimately inhibiting OC cell proliferation, migration, and invasion, thereby demonstrating the potential for developing novel anti-OC drugs. Clinical translation is still limited by inefficient extraction, low bioavailability, incomplete mechanistic characterization and a lack of clinical validation. Based on the current evidence and the aforementioned bottlenecks, this review offers a development path for natural glycolysis inhibitors in precision anti-OC therapy.