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<p>Macrophage polarization shapes immune responses in inflammation and fibrosis, yet the epigenetic mechanisms restraining pathogenic states remain unclear. Here, we identify lysine-specific demethylase 7 A (KDM7A) as an epigenetic suppressor of a profibrotic macrophage (Fib-Mac). Using macrophage assays, single-cell RNA sequencing of Kdm7a-knockout mice, and lung tissue from fibrosis patients, we show that Kdm7a loss drives transcriptional and metabolic reprogramming toward Fib-Mac states. Kdm7a-knockout mice exhibit exacerbated bleomycin-induced lung fibrosis with the expansion of Fib-Mac populations. Mechanistically, we identify toll-like receptor 8 (TLR8) as a suppressor of Fib-Mac polarization whose expression is regulated by KDM7A <i>via</i> the repressive mark H3K27me2 at its enhancer. Notably, macrophage Kdm7a and Tlr8 expression declines with age in male mice, consistent with clinical risk patterns. These findings uncover an epigenetic mechanism restraining disease-driving macrophage states and suggest the KDM7A-TLR8 axis as a potential therapeutic target in fibrotic disorders.</p><p></p>

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Histone demethylase KDM7A negatively regulates fibrotic macrophage polarization and lung fibrosis progression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月23日

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  • Naofumi Funagura,
  • Tomoaki Koga,
  • Kan Etoh,
  • Seonghyeon Hong,
  • Hidenori Ichiyasu,
  • Yukio Fujijwara,
  • Kei-ichiro Yasunaga,
  • Shingo Usuki,
  • Ayane Noda,
  • Akihito Sagara,
  • Shinjiro Hino,
  • Yoshihiro Komohara,
  • Takuro Sakagami,
  • Toshihiro Inoue,
  • Mitsuyoshi Nakao

摘要

Macrophage polarization shapes immune responses in inflammation and fibrosis, yet the epigenetic mechanisms restraining pathogenic states remain unclear. Here, we identify lysine-specific demethylase 7 A (KDM7A) as an epigenetic suppressor of a profibrotic macrophage (Fib-Mac). Using macrophage assays, single-cell RNA sequencing of Kdm7a-knockout mice, and lung tissue from fibrosis patients, we show that Kdm7a loss drives transcriptional and metabolic reprogramming toward Fib-Mac states. Kdm7a-knockout mice exhibit exacerbated bleomycin-induced lung fibrosis with the expansion of Fib-Mac populations. Mechanistically, we identify toll-like receptor 8 (TLR8) as a suppressor of Fib-Mac polarization whose expression is regulated by KDM7A via the repressive mark H3K27me2 at its enhancer. Notably, macrophage Kdm7a and Tlr8 expression declines with age in male mice, consistent with clinical risk patterns. These findings uncover an epigenetic mechanism restraining disease-driving macrophage states and suggest the KDM7A-TLR8 axis as a potential therapeutic target in fibrotic disorders.