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<p>While α-ketoglutarate (α-KG) has traditionally been viewed as an anti-inflammatory metabolite, we uncover its paradoxical role in driving pathological inflammation during sepsis. This study reveals that α-KG, a tricarboxylic acid cycle (TCA) intermediate elevated in septic patients, drives inflammatory macrophage death through absent in melanoma 2 (AIM2) -PANoptosome activation. Using both clinical samples and experimental models, we demonstrate that the cell-permeable derivative dimethyl-α-ketoglutarate (DM-α-KG) exacerbates lipopolysaccharide (LPS)-induced tissue injury and cell death, whereas isocitrate dehydrogenase (IDH1) inhibition (IDH-305) or genetic ablation reduces α-KG levels and confers protection. Mechanistically, α-KG enhances the dioxygenase activity of Ten-eleven translocation 2 (TET2), promoting its binding to the AIM2 promoter, reducing methylation, and increasing AIM2 expression, thereby triggering PANoptosome assembly. The pathophysiological relevance of this axis was confirmed by attenuated inflammation following either TET inhibition (dimethyloxallyl glycine, DMOG) or AIM2 deletion. These findings establish α-KG as a critical immunometabolic checkpoint in sepsis that licenses inflammatory cell death via TET2-mediated epigenetic control of AIM2. Our work not only elucidates a novel α-KG/TET2/AIM2 signaling axis in sepsis pathogenesis but also highlights the therapeutic potential of targeting this pathway to modulate immune responses.</p> Graphical Abstract <p>In sepsis, LPS challenge upregulates IDH1 expression, leading to the accumulation of α-KG. This increase in α-KG enhances dioxygenase activity of TET2, and promotes its recruitment to the <i>AIM2 </i>promoter, where it catalyzes local DNA demethylation and drives <i>AIM2 </i>transcription. The upregulated AIM2 protein then recruits the adaptor ASC to assemble the PANoptosome, a multiprotein complex that integrates key effector molecules from apoptosis, necroptosis, and pyroptosis pathways. This platform coordinately activates all three forms of programmed cell death, resulting in PANoptosis, a potent inflammatory cell death modality.Ultimately, this signaling cascade exacerbates multi-organ injury, a hallmark of severe sepsis.</p> <p></p>

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The metabolite α-ketoglutarate induces AIM2-dependent PANoptosis through demethylase TET2

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月16日

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  • Yi Li,
  • Qing Tu,
  • Chenchen Liu,
  • Jiamin Ma,
  • Yuwei Chen,
  • Lin Wang,
  • Ying Chen,
  • Jinbao Li,
  • Jiali Zhu,
  • Yun Zou,
  • Liangfang Yao

摘要

While α-ketoglutarate (α-KG) has traditionally been viewed as an anti-inflammatory metabolite, we uncover its paradoxical role in driving pathological inflammation during sepsis. This study reveals that α-KG, a tricarboxylic acid cycle (TCA) intermediate elevated in septic patients, drives inflammatory macrophage death through absent in melanoma 2 (AIM2) -PANoptosome activation. Using both clinical samples and experimental models, we demonstrate that the cell-permeable derivative dimethyl-α-ketoglutarate (DM-α-KG) exacerbates lipopolysaccharide (LPS)-induced tissue injury and cell death, whereas isocitrate dehydrogenase (IDH1) inhibition (IDH-305) or genetic ablation reduces α-KG levels and confers protection. Mechanistically, α-KG enhances the dioxygenase activity of Ten-eleven translocation 2 (TET2), promoting its binding to the AIM2 promoter, reducing methylation, and increasing AIM2 expression, thereby triggering PANoptosome assembly. The pathophysiological relevance of this axis was confirmed by attenuated inflammation following either TET inhibition (dimethyloxallyl glycine, DMOG) or AIM2 deletion. These findings establish α-KG as a critical immunometabolic checkpoint in sepsis that licenses inflammatory cell death via TET2-mediated epigenetic control of AIM2. Our work not only elucidates a novel α-KG/TET2/AIM2 signaling axis in sepsis pathogenesis but also highlights the therapeutic potential of targeting this pathway to modulate immune responses.

Graphical Abstract

In sepsis, LPS challenge upregulates IDH1 expression, leading to the accumulation of α-KG. This increase in α-KG enhances dioxygenase activity of TET2, and promotes its recruitment to the AIM2 promoter, where it catalyzes local DNA demethylation and drives AIM2 transcription. The upregulated AIM2 protein then recruits the adaptor ASC to assemble the PANoptosome, a multiprotein complex that integrates key effector molecules from apoptosis, necroptosis, and pyroptosis pathways. This platform coordinately activates all three forms of programmed cell death, resulting in PANoptosis, a potent inflammatory cell death modality.Ultimately, this signaling cascade exacerbates multi-organ injury, a hallmark of severe sepsis.