PYCR2 contributes to sunitinib resistance in hepatocellular carcinoma by activating the PPAR signaling pathway

Objective: This study investigates the role of Pyrroline-5-carboxylate reductase 2 (PYCR2) in hepatocellular carcinoma (HCC) progression, and Sunitinib resistance.

Methods: PYCR2 expression in HCC was profiled via TCGA, GEO, and ICGC datasets, and the relevant genes were analyzed by GO and KEGG enrichment. Genomic analyses linked PYCR2 levels to genomic instability and immune responses, while CTRP data evaluated drug sensitivity. In vitro and in vivo studies examined PYCR2-mediated Sunitinib resistance in HCC cells and the role of PPAR signaling in this process.

Results: PYCR2 was significantly overexpressed in HCC, correlating with poor survival outcomes. And PYCR2 exhibited higher expression in patients responding to anti-PD-1 therapy. GO and KEGG analyses revealed PYCR2-related genes were positively enriched in metabolism-related biological processes and pathways. Genomic analysis revealed a higher frequency of mutations and copy number variations in high-PYCR2 group. Immune profiling highlighted strong correlations between PYCR2 and immune cell infiltration and related gene expression. Drug sensitivity analysis indicated a positive correlation between PYCR2 and Sunitinib resistance. In vitro, PYCR2 upregulated PPARα/γ and RXRα under sunitinib treatment, attenuated Apoptosis, and restored clonogenic growth in vitro; In vivo, PYCR2 overexpression impaired sunitinib efficacy, accompanied by increased Ki67, PPARα/γ.

Conclusion: PYCR2 promotes HCC progression and Sunitinib resistance via the PPAR signaling pathway, involving regulation of metabolism, immunity, and genomic stability. These findings highlight PYCR2 as a promising therapeutic target for overcoming tyrosine kinase inhibitors resistance in HCC.