Fumarate activates the IL-6/JAK/STAT3 pathway by inhibiting KDM4C-mediated H3K36me3 demethylation in FH-knockdown renal cancer cells

Fumarate is a small molecule metabolite that plays a key role in the malignant transformation of cells, yet the underlying mechanism remains unclear. Herein, we discovered that accumulated fumarate in fumarate hydratase (FH)-knockdown ACHN and HK-2 cells competitively binds to α-ketoglutaric acid (α-KG), effectively inhibiting the activity of the histone demethylase KDM4C and significantly increasing the level of histone 3 lysine 36 trimethylation (H3K36me3). The upregulation of H3K36me3 expression triggered the activation of the IL-6/JAK/STAT3 oncogenic signaling pathway and increased the expression of the chemokine CXCL10. Phosphorylated STAT3 (p-STAT3) further enhanced programmed cell death ligand 1 (PD-L1) expression. Therefore, our study identified a novel regulatory mechanism in FH-knockdown cells in which fumarate accumulation inhibits KDM4C activity, resulting in epigenetic and gene expression dysregulation. Collectively, these findings suggest that combining immune checkpoint blockade (ICB) with a STAT3 inhibitor may hold promise for patients with fumarate hydratase-deficient renal cell carcinoma.