Scholarlink

Background <p>Triple negative breast cancer (TNBC), characterized by its aggressive clinical behavior and propensity for distant metastasis, presents critical challenges in therapeutic management. Emerging evidence implicates lipid metabolic reprogramming as a key facilitator of tumor progression and metastatic dissemination. However, the precise molecular mechanisms underlying lipid metabolic dysregulation in TNBC metastasis remain poorly characterized. Our work systematically elucidates the mechanistic role of ALDH3A2 in orchestrating lipid metabolic adaptations that drive breast cancer metastasis.</p> Methods <p>Transcriptomic analysis of clinical datasets identified metastasis-related metabolic regulators. Cellular migration/invasion assays and murine metastasis models were utilized to assess metastatic effects of ALDH3A2. Lipidomic profiling coupled with pathway analysis characterized metabolic alterations. Mechanistic studies integrated western blot analysis with lipid droplet quantification. Computational approaches including structure-based virtual screening and molecular docking simulations were employed for inhibitor discovery.</p> Results <p>ALDH3A2 was significantly upregulated in TNBC clinical specimens and showed significant association with adverse clinical outcomes. Functional validation confirmed that ALDH3A2 potentiates TNBC cell migration/invasion through epithelial-mesenchymal transition (EMT) activation. Metabolic profiling revealed ALDH3A2-driven lipid accumulation, evidenced by increased lipid droplet formation and elevated triglyceride levels. Specifically, arachidonic acid (AA) enrichment was observed in ALDH3A2-overexpressing cells, corresponding to enhanced glycerophospholipid metabolism. Mechanistic studies demonstrated that ALDH3A2-mediated AMP/ATP imbalance suppresses AMPK phosphorylation while activating mTOR/SREBP1 signaling. mTOR inhibition effectively attenuated ALDH3A2-induced lipid metabolic alterations. Importantly, oxaliplatin was identified as a potential therapeutic agent targeting ALDH3A2-mediated AA metabolism to suppress metastasis.</p> Conclusions <p>Our work establishes ALDH3A2 as a pivotal regulator of lipid metabolic reprogramming in TNBC metastasis, providing mechanistic insights into AA-mediated tumor progression. These findings position ALDH3A2 as a promising therapeutic target and prognostic biomarker for TNBC management.</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

ALDH3A2 targets arachidonic acid to promote cell metastasis in TNBC via AMPK/m-TOR signaling pathway

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月18日

查看全文
  • Ding Wang,
  • Shulei Luo,
  • Rongji Yu,
  • Doudou Wen,
  • Hao Jiang,
  • Keli Xu,
  • Xiaotang Di,
  • Shubing Zhang

摘要

Background

Triple negative breast cancer (TNBC), characterized by its aggressive clinical behavior and propensity for distant metastasis, presents critical challenges in therapeutic management. Emerging evidence implicates lipid metabolic reprogramming as a key facilitator of tumor progression and metastatic dissemination. However, the precise molecular mechanisms underlying lipid metabolic dysregulation in TNBC metastasis remain poorly characterized. Our work systematically elucidates the mechanistic role of ALDH3A2 in orchestrating lipid metabolic adaptations that drive breast cancer metastasis.

Methods

Transcriptomic analysis of clinical datasets identified metastasis-related metabolic regulators. Cellular migration/invasion assays and murine metastasis models were utilized to assess metastatic effects of ALDH3A2. Lipidomic profiling coupled with pathway analysis characterized metabolic alterations. Mechanistic studies integrated western blot analysis with lipid droplet quantification. Computational approaches including structure-based virtual screening and molecular docking simulations were employed for inhibitor discovery.

Results

ALDH3A2 was significantly upregulated in TNBC clinical specimens and showed significant association with adverse clinical outcomes. Functional validation confirmed that ALDH3A2 potentiates TNBC cell migration/invasion through epithelial-mesenchymal transition (EMT) activation. Metabolic profiling revealed ALDH3A2-driven lipid accumulation, evidenced by increased lipid droplet formation and elevated triglyceride levels. Specifically, arachidonic acid (AA) enrichment was observed in ALDH3A2-overexpressing cells, corresponding to enhanced glycerophospholipid metabolism. Mechanistic studies demonstrated that ALDH3A2-mediated AMP/ATP imbalance suppresses AMPK phosphorylation while activating mTOR/SREBP1 signaling. mTOR inhibition effectively attenuated ALDH3A2-induced lipid metabolic alterations. Importantly, oxaliplatin was identified as a potential therapeutic agent targeting ALDH3A2-mediated AA metabolism to suppress metastasis.

Conclusions

Our work establishes ALDH3A2 as a pivotal regulator of lipid metabolic reprogramming in TNBC metastasis, providing mechanistic insights into AA-mediated tumor progression. These findings position ALDH3A2 as a promising therapeutic target and prognostic biomarker for TNBC management.