Tumor cell-derived IL-23 promotes hepatocellular carcinoma progression via an autocrine IL-23/EGFR/AKT signaling axis

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, with metastasis and recurrence representing major clinical challenges. Although the pro-inflammatory cytokine interleukin-23 (IL-23) has been implicated in tumor progression, its tumor cell-autonomous function in HCC remains poorly understood. This study aims to elucidate the role and underlying mechanisms of autocrine IL-23 in HCC pathogenesis.

Public databases and patient tissue samples were analyzed to evaluate the expression of IL-23. IL-23 receptor (IL-23R)-knockdown and stable IL-23-overexpression HCC cell lines were established to assess the functional impact of IL-23 on proliferation, clonogenicity, and migration. Transcriptomic profiling via RNA sequencing was performed, followed by GO, KEGG, and GSEA analyses to identify altered signaling pathways. The key molecules within the IL-23-mediated signaling pathway were further validated through functional assays and Western Blot analysis.

IL-23 expression was significantly upregulated in HCC tumors, with further elevation in metastatic lesions. Knockdown of IL-23R inhibited proliferation, clonogenicity, and migration of HCC cells, while endogenous IL-23 overexpression enhanced these phenotypes. The transcriptomic analyses showed enrichment of several oncogenic signaling pathways, including TGF-β, JAK/STAT, Hippo, MAPK and PI3K/AKT/mTOR. Mechanistically, IL-23 overexpression increased EGFR, AKT and p-AKT expression, defining a novel IL-23/EGFR/AKT signaling axis that drives malignant phenotypes.

Autocrine IL-23 promotes HCC progression by enhancing proliferative and metastatic capacities through activation of multiple oncogenic pathways, particularly the autocrine IL-23/EGFR/AKT axis, nominating IL-23 as a therapeutic target.