Scholarlink

Background <p>Ferroptosis is an iron-dependent form of regulated cell death driven by the accumulation of lipid peroxides. Lactylation, a post-translational modification derived from metabolic reprogramming, whether it drives non-small cell lung cancer (NSCLC) progression by regulating ferroptosis remains unclear. This study aims to elucidate the role and underlying mechanism by which β-catenin lactylation regulates ferroptosis to drive NSCLC progression, offering novel insights into disease pathogenesis and potential therapeutic targeting.</p> Methods <p>Blood, tumor tissues, and adjacent normal tissues from NSCLC patients were collected to detect lactate levels and protein lactylation using biochemical assays, Western blot, and immunofluorescence. Cell models were established in BEAS-2B and NSCLC cell lines, with lactylation regulated by lactate (LA) and 2-deoxyglucose (2-DG). Cellular proliferation, migration, and invasion were quantified using CCK-8, EdU incorporation, Transwell chamber, and wound healing assays, respectively. Ferroptosis was assessed by detecting LPO and GSH levels, and transmission electron microscopy. β-catenin lactylation sites were identified by mass spectrometry and site-directed mutagenesis. β-catenin, TCF4, and GPX4 expression at protein and mRNA levels was detected by Western blot and qRT-PCR. ChIP verified the binding of β-catenin/TCF4 complex to the GPX4 promoter. Nude mouse subcutaneous xenograft models were used to validate in vivo tumor growth regulation, with immunofluorescence detecting β-catenin lactylation and GPX4 expression in tumors.</p> Results <p>NSCLC clinical samples showed elevated lactate levels, global protein lactylation, and β-catenin lactylation at lysine 193 (K193) compared to controls. β-catenin K193 lactylation enhanced protein stability, promoting NSCLC cell proliferation, migration, and invasion, which was reversed by 2-DG. LA accelerated tumor growth in nude mice, while 2-DG inhibited it. Mechanistically, β-catenin K193 lactylation reduced LPO and increased GSH to suppress ferroptosis: lactylated β-catenin translocated to the nucleus, formed a complex with TCF4, and upregulated GPX4 transcription by binding its promoter. GPX4 overexpression reversed ferroptosis induced by β-catenin K193 lactylation inhibition, while blocking β-catenin/TCF4 interaction downregulated GPX4 and enhanced ferroptosis.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Lactylation of β-catenin promotes non-small cell lung cancer by inhibiting ferroptosis through TCF4-mediated GPX4 transcription

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月14日

查看全文
  • Xuefeng Yang,
  • Cuicui Guo,
  • Yingying Lu,
  • Ran Zhou,
  • Zilei Liu,
  • Zhongxin Yang,
  • Shun Xu,
  • Wei Li

摘要

Background

Ferroptosis is an iron-dependent form of regulated cell death driven by the accumulation of lipid peroxides. Lactylation, a post-translational modification derived from metabolic reprogramming, whether it drives non-small cell lung cancer (NSCLC) progression by regulating ferroptosis remains unclear. This study aims to elucidate the role and underlying mechanism by which β-catenin lactylation regulates ferroptosis to drive NSCLC progression, offering novel insights into disease pathogenesis and potential therapeutic targeting.

Methods

Blood, tumor tissues, and adjacent normal tissues from NSCLC patients were collected to detect lactate levels and protein lactylation using biochemical assays, Western blot, and immunofluorescence. Cell models were established in BEAS-2B and NSCLC cell lines, with lactylation regulated by lactate (LA) and 2-deoxyglucose (2-DG). Cellular proliferation, migration, and invasion were quantified using CCK-8, EdU incorporation, Transwell chamber, and wound healing assays, respectively. Ferroptosis was assessed by detecting LPO and GSH levels, and transmission electron microscopy. β-catenin lactylation sites were identified by mass spectrometry and site-directed mutagenesis. β-catenin, TCF4, and GPX4 expression at protein and mRNA levels was detected by Western blot and qRT-PCR. ChIP verified the binding of β-catenin/TCF4 complex to the GPX4 promoter. Nude mouse subcutaneous xenograft models were used to validate in vivo tumor growth regulation, with immunofluorescence detecting β-catenin lactylation and GPX4 expression in tumors.

Results

NSCLC clinical samples showed elevated lactate levels, global protein lactylation, and β-catenin lactylation at lysine 193 (K193) compared to controls. β-catenin K193 lactylation enhanced protein stability, promoting NSCLC cell proliferation, migration, and invasion, which was reversed by 2-DG. LA accelerated tumor growth in nude mice, while 2-DG inhibited it. Mechanistically, β-catenin K193 lactylation reduced LPO and increased GSH to suppress ferroptosis: lactylated β-catenin translocated to the nucleus, formed a complex with TCF4, and upregulated GPX4 transcription by binding its promoter. GPX4 overexpression reversed ferroptosis induced by β-catenin K193 lactylation inhibition, while blocking β-catenin/TCF4 interaction downregulated GPX4 and enhanced ferroptosis.