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<p>Tissue regeneration is essential for maintaining tissue homoeostasis and influences disease progression. In the liver, injury evokes a complex regenerative response with robust immune activation and metabolic rewiring, yet how these processes coordinate hepatocyte proliferation remains unclear. Here we show the presence of an injury-induced, lipid-dependent accrual of a distinct monocyte-derived macrophage (MDM) subset characterized by abundant cytosolic lipid content and heightened inflammatory response. Multi-omic analyses, spanning both single-cell transcriptomics and quantitative lipidomics, unveil substantial cellular diversity and heterogeneity between these ‘lipo-inflammatory MDMs’ (termed LIMMs) and other hepatic macrophages, including Kupffer cells. Blocking CD36-dependent LIMM induction markedly impairs hepatocyte proliferation and liver regeneration in injured livers. Mechanistically, CD36-mediated increase in ceramide biosynthesis activates IRE1α–XBP1 signalling pathway in LIMMs, driving production of the regenerative cytokine interleukin-6. Disrupting CD36-dependent IRE1α activation in LIMMs compromises liver repair. These findings identify a lipid-laden MDM subcluster as a key regulator of regenerative inflammation in injured livers.</p>

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Lipid-dependent accrual of a subset of monocyte-derived macrophages is essential for tissue regeneration

  • 期刊论文

  • 发表日期：

    2026年3月11日

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  • Tao Yao,
  • Xin Tian,
  • Linbin Rao,
  • Jinling Ni,
  • Jiayong Yu,
  • Hongguo Yang,
  • Yuexiao Tang,
  • Xingxiao Huang,
  • Xintong Xia,
  • Lin Zhao,
  • Bowen Diao,
  • Yan Ping,
  • Danni Wei,
  • Siqi Li,
  • Hui Chai,
  • Zhiming Hu,
  • Xiongzhong Ruan,
  • Suihan Feng,
  • Mengle Shao,
  • Bo Shan,
  • Ying Wu

摘要

Tissue regeneration is essential for maintaining tissue homoeostasis and influences disease progression. In the liver, injury evokes a complex regenerative response with robust immune activation and metabolic rewiring, yet how these processes coordinate hepatocyte proliferation remains unclear. Here we show the presence of an injury-induced, lipid-dependent accrual of a distinct monocyte-derived macrophage (MDM) subset characterized by abundant cytosolic lipid content and heightened inflammatory response. Multi-omic analyses, spanning both single-cell transcriptomics and quantitative lipidomics, unveil substantial cellular diversity and heterogeneity between these ‘lipo-inflammatory MDMs’ (termed LIMMs) and other hepatic macrophages, including Kupffer cells. Blocking CD36-dependent LIMM induction markedly impairs hepatocyte proliferation and liver regeneration in injured livers. Mechanistically, CD36-mediated increase in ceramide biosynthesis activates IRE1α–XBP1 signalling pathway in LIMMs, driving production of the regenerative cytokine interleukin-6. Disrupting CD36-dependent IRE1α activation in LIMMs compromises liver repair. These findings identify a lipid-laden MDM subcluster as a key regulator of regenerative inflammation in injured livers.