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<p>Gastric cancer, the fifth most common malignancy worldwide, is characterized by poor prognosis due to its aggressive progression and therapeutic resistance, largely driven by the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs), as the predominant stromal component, contribute to tumor progression, metastasis, and chemoresistance through metabolic reprogramming and epigenetic modifications. Here, we investigated the role of Sonic Hedgehog (SHH) signaling in regulating ATP-citrate lyase (ACLY)-dependent acetyl-CoA metabolism and histone acetylation during gastric CAF activation. Primary CAFs exhibited elevated fibroblast activation markers (FAP1, α-SMA) compared to normal gastric fibroblasts (NFs). SHH stimulation or co-culture with gastric cancer cells robustly upregulated ACLY transcription and protein expression in NFs, synergistically enhancing acetyl-CoA production. Genetic ACLY knockdown or pharmacologic inhibition attenuated SHH-induced CAF activation markers (α-SMA, FAP1, FSP1) and reduced intracellular acetyl-CoA levels by &gt; 50%, concomitant with diminished global histone H3 acetylation. Chromatin immunoprecipitation revealed SHH-driven enrichment of H3 acetylation at promoters of CAF marker genes, which was reversed by ACLY silencing or histone acetyltransferase inhibition. Moreover, tumor cell-conditioned medium recapitulated these metabolic-epigenetic changes in NFs. Our findings establish SHH/ACLY/acetyl-CoA as a novel axis linking stromal metabolism to epigenetic reprogramming in gastric CAFs, wherein ACLY-generated acetyl-CoA fuels histone acetylation to activate pro-tumorigenic transcriptional programs. This study unveils a therapeutically targetable mechanism underlying TME remodeling, positioning ACLY as a stromal metabolic checkpoint in gastric cancer progression.</p> Graphical Abstract <p></p>

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SHH drives gastric cancer-associated fibroblast activation via ACLY-dependent acetyl-CoA metabolism and histone acetylation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月2日

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  • Xianhu Zhang,
  • Longhe Sun,
  • Youlei Zhang,
  • Yulong Wang,
  • Yong Huang,
  • Yongjun Jiang,
  • Daorong Wang

摘要

Gastric cancer, the fifth most common malignancy worldwide, is characterized by poor prognosis due to its aggressive progression and therapeutic resistance, largely driven by the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs), as the predominant stromal component, contribute to tumor progression, metastasis, and chemoresistance through metabolic reprogramming and epigenetic modifications. Here, we investigated the role of Sonic Hedgehog (SHH) signaling in regulating ATP-citrate lyase (ACLY)-dependent acetyl-CoA metabolism and histone acetylation during gastric CAF activation. Primary CAFs exhibited elevated fibroblast activation markers (FAP1, α-SMA) compared to normal gastric fibroblasts (NFs). SHH stimulation or co-culture with gastric cancer cells robustly upregulated ACLY transcription and protein expression in NFs, synergistically enhancing acetyl-CoA production. Genetic ACLY knockdown or pharmacologic inhibition attenuated SHH-induced CAF activation markers (α-SMA, FAP1, FSP1) and reduced intracellular acetyl-CoA levels by > 50%, concomitant with diminished global histone H3 acetylation. Chromatin immunoprecipitation revealed SHH-driven enrichment of H3 acetylation at promoters of CAF marker genes, which was reversed by ACLY silencing or histone acetyltransferase inhibition. Moreover, tumor cell-conditioned medium recapitulated these metabolic-epigenetic changes in NFs. Our findings establish SHH/ACLY/acetyl-CoA as a novel axis linking stromal metabolism to epigenetic reprogramming in gastric CAFs, wherein ACLY-generated acetyl-CoA fuels histone acetylation to activate pro-tumorigenic transcriptional programs. This study unveils a therapeutically targetable mechanism underlying TME remodeling, positioning ACLY as a stromal metabolic checkpoint in gastric cancer progression.

Graphical Abstract