Aloe vera extract co-treatment in hepatocellular carcinoma increases cisplatin sensitivity by shifting energy metabolism from glycolysis to oxidative phosphorylation and inhibiting key resistance mechanisms

Backround: A significant challenge in hepatocellular carcinoma (HCC) therapy is cisplatin resistance, often linked to altered energy metabolism, specifically the Warburg effect (aerobic glycolysis). This study investigates the potential of Aloe vera extract (AVE) to overcome this resistance and enhance cisplatin's efficacy. Methods: The effects of AVE, cisplatin, and their combination (CisAVE) on HepG2 cells were assessed using oxygen consumption assays, real-time cell analysis (RTCA), wound healing assays, and transcriptomic sequencing with functional enrichment analysis. Results: Treatment with CisAVE induced a significant metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS), as indicated by increased oxygen consumption. This shift promoted reactive oxygen species (ROS) production and initiated apoptosis, evidenced by the upregulation of pro-apoptotic genes (FAS, NOXA, PUMA). While AVE's antiproliferative effect occurred later than cisplatin's due to its ATP-dependent mechanism, it demonstrated superior antimigratory effects. Crucially, AVE downregulated LUC7L3, a key gene associated with cisplatin resistance. Transcriptomic analysis further revealed activation of detoxification pathways and modulation of processes suggesting a protective effect against cisplatin-induced hepatorenal toxicity. Conclusion: Our findings demonstrate that Aloe vera extract re-sensitizes cisplatin-resistant HCC cells by reversing the Warburg effect, inducing metabolic reprogramming towards OXPHOS, and suppressing the cisplatin resistance marker LUC7L3. This combination strategy presents a promising multi-faceted approach to overcome chemoresistance in HCC.