CKS2 Mediates Hepatocellular Carcinoma Recurrence After Hepatic Ischemia-Reperfusion Injury Related to M2 Macrophages

PURPOSE: Hepatocellular carcinoma (HCC) recurrence remains a significant burden on global healthcare. Hepatic ischemia-reperfusion injury (HIRI) is a common complication in liver surgery and may be a contributing factor to HCC recurrence. Nevertheless, the potential mechanism underlying HIRI-induced HCC recurrence has not been fully elucidated. Herein, by combining bioinformatics approaches and basic experimental research, CKS2 was preliminarily identified as a crucial factor involved in HIRI-induced HCC recurrence potentially by modulating M2 macrophages. METHODS: Through performing Weighted Gene Co-Expression Network Analysis (WGCNA), differential gene expression analysis, and screening for genes associated with disease-free survival (DFS) on large-scale genomics projects including The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), the pivotal role of CKS2 in HIRI-induced HCC recurrence was determined. The clinical significance, single-cell analysis, immune cell infiltration correlation, functional enrichment, mutation landscape, and drug sensitivity of CKS2 in HCC were further characterized. Finally, CKS2 expression and function were validated through experimental techniques such as flow cytometry, immunohistochemistry, Western blot assay and quantitative real-time PCR (qRT-PCR). RESULTS: The expression of CKS2 was significantly upregulated in HIRI and HCC tissues and was closely associated with adverse clinical outcomes in HCC patients. There was a positive correlation between CKS2 expression and tumor stemness characteristics. Additionally, high CKS2 expression was strongly linked to M2 macrophage infiltration in HCC tissues. And drug sensitivity analysis indicated that HCC patients with high CKS2 expression were prone to develop drug resistance, complicating clinical anti-tumor treatment. Ultimately, the expression pattern of CKS2 and its correlation with M2 macrophages in HCC were confirmed through experimental validation. CONCLUSION: CKS2 was identified as a key factor in HIRI-induced HCC recurrence and was critically associated with M2 macrophage infiltration abundance, providing novel insights and a direction for future research.