Integrated analyses reveal a potential role for PFKFB4 in M2 macrophage polarization and hepatocellular carcinoma...

Hepatocellular carcinoma (HCC) is the third most lethal malignant tumor worldwide, PFKFB4 has emerged as a key metabolic enzyme with critical roles in cancer progression and immune regulation. However, its precise role in hepatocellular carcinoma remains unclear.

In this study, we performed integrated analyses, including single-cell transcriptomics, bioinformatics, enrichment analysis, in vitro functional assays, and in vivo validation, to explore the role of PFKFB4 in HCC progression and its influence on macrophage polarization.

Single-cell transcriptomic analysis identified elevated PFKFB4 expression in macrophages, correlating significantly with M2 polarization markers. Functional assays demonstrated that knockdown of PFKFB4 suppressed HCC cell proliferation, migration, and promoted apoptosis, while its overexpression exhibited the opposite effects. Mechanistically, inhibition of PFKFB4 reduced activation of the MEK/ERK signaling pathway, suggesting this pathway as a potential mediator. Additionally, Co-culture experiments revealed that knockdown of PFKFB4 in tumor cells led to a reduced M2 polarization of macrophages, suggesting its role in immune modulation.

Collectively, our findings indicate that PFKFB4 drives hepatocellular carcinoma progression through activation of the MEK/ERK signaling pathway and, in parallel, influences tumor progression via tumor cell-mediated modulation of M2 macrophage polarization.