Role of IGF-1-mediated FOXO signaling pathway in liver regeneration after ALPPS in rat models

doi:10.3877/cma.j.issn.2095-3232.2025010

Abstract

Abstract:

Objective

To investigate the role of FOXO signaling pathway mediated by IGF-1 in liver regeneration after the associating liver partition and portal vein ligation for staged hepatectomy(ALPPS) in rat models.

Methods

36 male Wistar rats were raised in SPF-grade laboratory environment,and all procedures met the requirements of laboratory animal ethics.Wistar rat models of ALPPS (ALPPS group), portal vein ligation (PVL group) and sham surgery (Sham group) were established.The regeneration of liver tissues at postoperative 24, 48 and 72 h was observed by Ki-67 immunohistochemical staining.At postoperative 72 h, transcriptome sequencing was performed in liver tissues.The key gene of insulinlike growth factor (IGF-1) was screened by bioinformatics methods such as weighted gene co-expression network analysis (WGCNA) and KEGG enrichment analysis.The relative expression of IGF-1 in rat liver was validated by RT-qPCR.Comparison among three groups was conducted by one-way ANOVA and LSD-t test.

Results

Immunohistochemical staining showed that the number of Ki-67 positive cells in liver tissues in the ALPPS and PVL groups was gradually increased at postoperative 24, 48 and 72 h, and the expression level of Ki-67 at postoperative 72 h was the highest in the ALPPS group (F=927.28, P＜0.05), significantly higher than those in the PVL and Sham groups (LSD-t=13.45, 42.15; both P＜0.05).The genes were divided into six modules by WGCNA, and the blue KMEblue module showed the highest correlation with ALPPS(r=0.69, P=0.002).Analysis of the blue module (containing 4 073 genes) showed that IGF-1 gene showed the highest connectivity in this module.KEGG enrichment analysis revealed 10 related signaling pathways, and found that FOXO, P53 and cell cycle signaling pathways were intimately correlated with liver regeneration.Among them, IGF-1 showed the highest connectivity in the FOXO signaling pathway.RT-qPCR indicated that compared with the PVL and Sham groups, the expression level of IGF-1 mRNA at postoperative 72 h was significantly up-regulated in the ALPPS group (F=4.989, P＜0.05), significantly higher than those in the PVL and Sham groups (LSD-t=2.43, 2.96; both P＜0.05).

Conclusions

IGF-1 in the FOXO signaling pathway may mediate liver regeneration after ALPPS in rats.

Key words: Hepatectomy, Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), Post-hepatectomy liver failure (PHLF), Liver regeneration, Insulin-like growth factor 1 (IGF-1), Signaling pathway

Bingcheng Meng, Hai Zhu, Hongbing Ren, Weimin Mao, Deling Wei, Banghao Xu, Jilong Wang, Zongrui Jin, Zhujing Lan, Keyu Huang, Tingting Lu, Ling Zhang, Ya Guo, Zhang Wen. Role of IGF-1-mediated FOXO signaling pathway in liver regeneration after ALPPS in rat models[J]. Chinese Journal of Hepatic Surgery(Electronic Edition), 2025, 14(01): 118-125.

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Figures/Tables 7

References 32

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基因	F	R
Rat-IGF-1	TGAGCGCACCTCCAATAAAGAT	TTGGTCCACACACGAACTGAAG
Rat-β-actin	ATCCTGCGTCTGGACCTGG	CCGCTCATTGCCGATAGTG

基因	F	R
Rat-IGF-1	TGAGCGCACCTCCAATAAAGAT	TTGGTCCACACACGAACTGAAG
Rat-β-actin	ATCCTGCGTCTGGACCTGG	CCGCTCATTGCCGATAGTG

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