FBXO22 promotes hepatocellular carcinoma progression via paracrine myo‑inositol‑induced M2‑type polarization of macrophages.

Macrophages play a key role in hepatocellular carcinoma (HCC) progression, but the mechanisms underlying this involvement remain unclear. In the present study, mice with HCC were used for experiments, and 97H and THP‑1 cells were used for experiments. Metabolomic analysis was performed to detect changes of metabolites in the supernatant of 97H cells. Flow cytometry and immunohistochemical staining were performed to assess macrophage polarization. Western blotting was performed to examine the levels of phosphorylated (p‑) PI3K, p‑AKT and NRF2. Reverse transcription‑quantitative polymerase chain reaction was performed to examine , and mRNA expression levels. FBXO22 significantly promoted the release of myo‑inositol in the cell supernatant of 97H cells, markedly decreased the number of CD86‑positive cells (M1 macrophages), and increased the number of CD206‑positive cells (M2 macrophages) in both THP‑1 cells and mouse HCC tumor tissues. The promoting effect of myo‑inositol on M2 macrophages was reversed by transfection with small interfering (si)‑SLC5A3 . In addition, FBXO22 overexpression reduced PTEN protein levels and then elevated NRF2 protein levels upregulating IMPA1 and inducing myo‑inositol release in 97H cells. Co‑culturing of 97H and THP‑1 cells revealed that the stimulatory effect of 97H cells transfected with an overexpression (oe)‑ construct on M2 macrophages was reversed by co‑transfection with the si‑. Co‑immunoprecipitation revealed a promoting effect of FBXO22 on PTEN ubiquitination via direct interaction in 97H cells. Furthermore, luciferase activity and chromatin immunoprecipitation assays indicated direct transcriptional regulation of IMPA1 expression by NRF2 in 97H cells. The experiments further revealed that transfection with the si‑ reversed the promoting effect of oe‑ on tumor growth and M2 polarization by reducing myo‑inositol levels in tumor tissues. In conclusion, FBXO22 degrades PTEN by inducing its ubiquitination to elevate NRF2 protein levels. As a result, IMPA1 expression is increased, which causes myo‑inositol release by HCC cells and further induces M2‑type macrophages via SLC5A3 to promote HCC tumor growth. The present study identified a novel molecular mechanism by which FBXO22 promotes HCC progression.