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.
Li et al. (Mon,) studied this question.