RPLP2 activates TLR4 in an autocrine manner and promotes HIF-1α-induced metabolic reprogramming in hepatocellular carcinoma

Abstract Metabolic reprogramming is a major feature of cancer, and aerobic glycolysis is one of the most widely studied metabolic reprogramming processes. Acidic ribosome protein P2 (RPLP2) is associated with both tumorigenesis and endoplasmic reticulum stress. However, limited knowledge exists regarding the role of RPLP2 in hepatocellular carcinoma (HCC) progression. In the present study, we observed a significant upregulation of RPLP2 in HCC tissues. Moreover, RPLP2 expression is closely correlated with patient prognosis and survival. The subsequent experimental validation demonstrated that RPLP2 exerted a regulatory effect on the expression of glycolytic enzymes and lactate production, thereby facilitating HCC cell proliferation. Mechanistically, the PI3K/AKT signalling pathway was found to play an important role in the regulation of hypoxia-inducible factor-1α (HIF-1α)-mediated aerobic glycolysis and cell growth. RPLP2 activates TLR4 on the surface of HCC cells and the downstream PI3K/AKT pathway through autocrine signalling. This activation then facilitates the entry of HIF-1α into the nucleus, enabling it to fulfil its transcriptional function. In conclusion, our findings suggested that RPLP2 induces a metabolic shift towards aerobic glycolysis and facilitates the progression of HCC through TLR4-dependent activation of the PI3K/AKT/HIF-1α pathway. Our study revealed the novel mechanism by which the ribosomal protein RPLP2 regulates glycolysis to promote HCC progression. These findings may offer a potential therapeutic target for HCC treatment.