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<p>Malignant cancers exhibit distinct lipid metabolic features that support tumor initiation and progression. Glioblastoma (GBM) is an aggressive brain tumor driven by GBM stem cells (GSCs), which are responsible for tumor development and therapy resistance. However, effective treatments targeting vulnerable metabolic pathways in GSCs have not yet been developed. Here, we demonstrate that the ATP-binding cassette transporter A3 (ABCA3) maintains lipid metabolic balance in GSCs. ABCA3 is highly expressed in GSCs, where lipid biosynthesis is particularly active. Knocking down <i>ABCA3</i> significantly reduces cell growth, self-renewal, viability, and tumor growth after intracranial implantation. These changes are caused by a profound disruption of lipid metabolic balance, as demonstrated by RNA sequencing and liquid chromatography-time-of-flight mass spectrometry, which revealed widespread alterations in lipid metabolism genes and lipid composition. Mechanistically, <i>ABCA3</i> knockdown inhibits sterol regulatory element-binding protein 1 (SREBP1) signaling by accumulating acylcarnitines (ACs) caused by phospholipid breakdown. The increased ACs induce the production of mitochondrial reactive oxygen species, which activate adenosine monophosphate-activated protein kinase (AMPK), resulting in the inhibition of SREBP1 signaling and reduced GSC fitness. Overall, these findings suggest that ABCA3 maintains lipid metabolic balance in GSCs, and disrupting this function triggers AMPK-dependent suppression of SREBP1 signaling.</p>

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Loss of ABCA3 disrupts lipid balance and leads to AMPK-dependent suppression of SREBP1 in glioblastoma stem cells

  • 期刊论文

  • 发表日期：

    2026年3月25日

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  • Jun-Kyum Kim,
  • Min Gi Park,
  • Seok Won Ham,
  • Seunghyun Yoon,
  • Sua Kim,
  • Junseok Jang,
  • Hyejin Kim,
  • Nayoung Hong,
  • Jong Min Park,
  • Cheol Gyu Park,
  • Min Ji Park,
  • Sang-Hun Choi,
  • Jung Yun Kim,
  • Hee-Young Jeon,
  • Sunyoung Seo,
  • Seon Yong Lee,
  • Yeri Lee,
  • Hee Jin Cho,
  • Minseo Gwak,
  • Eun-Jung Kim,
  • Kiyoung Eun,
  • Yong Jae Shin,
  • Do-Hyun Nam,
  • Se Hoon Kim,
  • Seung Jun Yoo,
  • Hyunggee Kim

摘要

Malignant cancers exhibit distinct lipid metabolic features that support tumor initiation and progression. Glioblastoma (GBM) is an aggressive brain tumor driven by GBM stem cells (GSCs), which are responsible for tumor development and therapy resistance. However, effective treatments targeting vulnerable metabolic pathways in GSCs have not yet been developed. Here, we demonstrate that the ATP-binding cassette transporter A3 (ABCA3) maintains lipid metabolic balance in GSCs. ABCA3 is highly expressed in GSCs, where lipid biosynthesis is particularly active. Knocking down ABCA3 significantly reduces cell growth, self-renewal, viability, and tumor growth after intracranial implantation. These changes are caused by a profound disruption of lipid metabolic balance, as demonstrated by RNA sequencing and liquid chromatography-time-of-flight mass spectrometry, which revealed widespread alterations in lipid metabolism genes and lipid composition. Mechanistically, ABCA3 knockdown inhibits sterol regulatory element-binding protein 1 (SREBP1) signaling by accumulating acylcarnitines (ACs) caused by phospholipid breakdown. The increased ACs induce the production of mitochondrial reactive oxygen species, which activate adenosine monophosphate-activated protein kinase (AMPK), resulting in the inhibition of SREBP1 signaling and reduced GSC fitness. Overall, these findings suggest that ABCA3 maintains lipid metabolic balance in GSCs, and disrupting this function triggers AMPK-dependent suppression of SREBP1 signaling.