Luteolin inhibits prostate cancer stem cells through disrupting the lactate/H3K18la/β-catenin/LDHA feedback loop.

Prostate cancer is one of the most common malignant tumors in men, with prostate cancer stem cells (PCSCs) playing an important role in its initiation and progression. Accumulating evidence has demonstrated that lactate and lactate-mediated histone lactylation are crucial regulators of proliferation, metastasis, immune escape and drug resistance in various cancer. However, their functional roles and underlying mechanisms in PCSCs remain largely elusive. In the present study, we found that lactate levels were significantly elevated in PCSC microenvironment, which effectively induced H3K18 lactylation (H3K18la). The increased-lactate enhanced the stemness of PCSCs. ChIP analysis revealed that H3K18la positively regulated the transcription of the β-catenin gene. Furthermore, β-catenin transcriptionally activated lactate dehydrogenase A (LDHA) to promote lactate production, thereby forming a lactate/H3K18la/β-catenin/LDHA positive feedback loop. Notably, luteolin, a natural flavone, disrupted this feedback loop and exerted potent inhibitory effects on PCSCs. Collectively, our findings uncover a novel lactate-driven regulatory axis in PCSCs and provide new insights into the development of intervention strategies in prostate cancer.