肝癌（LC）是世界上最致命的癌症之一，现有的治疗方法效果有限。本研究旨在阐明吡咯啉-5-羧酸还原酶1（PYCR1）作为LC潜在治疗靶点的作用和潜在机制。采用免疫组织化学和Western blot方法分析PYCR1在LC细胞和组织中的表达。采用EdU实验、集落形成实验、划痕愈合实验、Transwell实验、裸鼠异种移植模型和裸鼠肺转移模型检测LC细胞的生长和转移能力。利用转录组测序寻找PYCR1调控的下游靶基因，利用代谢组学鉴定PYCR1调控的下游代谢物。采用 ChIP 检测分析 IRS1 启动子区域 H3K18 乳酰化的富集情况。我们发现 HCC 中 PYCR1 的表达显着增加，并且这种高表达与 HCC 患者的不良预后相关。 PYCR1 的敲除或抑制可在体内和体外抑制 HCC 细胞的增殖、迁移和侵袭。此外，我们发现敲除或抑制 PYCR1 可以抑制 HCC 细胞中的糖酵解并减少 IRS1 组蛋白的 H3K18 乳酰化，从而抑制 IRS1 表达。我们的研究结果确定 PYCR1 是 LC 进展的关键调节因子，影响肿瘤细胞代谢和基因表达。通过证明靶向 PYCR1 抑制 LC 细胞增殖和转移的潜力，本研究确定 PYCR1 作为 LC 有前景的治疗靶点。Pyrroline-5-羧酸还原酶 1 (PYCR1) 促进肝癌 (LC) 细胞的增殖和转移。 LC 中 PYCR1 的表达受 DNA 甲基化调节。敲低或抑制 PYCR1 可抑制 LC 细胞中的糖酵解以及 PI3K/AKT/mTOR 和 MAPK/ERK 通路。 PYCR1 通过影响 IRS1 启动子区域的 H3K18 乳酰化来调节 IRS1 的转录活性。© 2024 作者。约翰·威利出版的《临床与转化医学》

Liver cancer (LC) is among the deadliest cancers worldwide, with existing treatments showing limited efficacy. This study aimed to elucidate the role and underlying mechanisms of pyrroline-5-carboxylate reductase 1 (PYCR1) as a potential therapeutic target in LC.Immunohistochemistry and Western blot were used to analyse the expression of PYCR1 in LC cells and tissues. EdU assays, colony-forming assays, scratch wound healing assays, Transwell assays, nude mouse xenograft models and nude mouse lung metastasis models were used to detect the growth and metastasis abilities of LC cells. Transcriptome sequencing was used to search for downstream target genes regulated by PYCR1, and metabolomics was used to identify the downstream metabolites regulated by PYCR1. ChIP assays were used to analyse the enrichment of H3K18 lactylation in the IRS1 promoter region.We found that the expression of PYCR1 was significantly increased in HCC and that this high expression was associated with poor prognosis in HCC patients. Knockout or inhibition of PYCR1 inhibited HCC cell proliferation, migration and invasion both in vivo and in vitro. In addition, we revealed that knocking out or inhibiting PYCR1 could inhibit glycolysis in HCC cells and reduce H3K18 lactylation of the IRS1 histone, thereby inhibiting IRS1 expression.Our findings identify PYCR1 as a pivotal regulator of LC progression that influences tumour cell metabolism and gene expression. By demonstrating the potential of targeting PYCR1 to inhibit LC cell proliferation and metastasis, this study identified PYCR1 as a promising therapeutic target for LC.Pyrroline-5-carboxylate reductase 1 (PYCR1) promotes the proliferation and metastasis of liver cancer (LC) cells. The expression of PYCR1 in LC is regulated by DNA methylation. Knocking down or inhibiting PYCR1 inhibits glycolysis as well as the PI3K/AKT/mTOR and MAPK/ERK pathways in LC cells. PYCR1 regulates the transcriptional activity of IRS1 by affecting H3K18 lactylation in its promoter region.© 2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.