Itaconate drives pro-inflammatory responses through proteasomal degradation of GLO1.

Summary

This mechanistic study shows that itaconate can exacerbate inflammation by inducing proteasomal degradation of GLO1 (via Cys139), thereby raising MGO and AGE levels and activating the AGE–RAGE pathway. Sepsis patient PBMCs exhibited higher itaconate with reduced GLO1, and in vivo targeting of AGER signaling improved survival in experimental sepsis.

Key Findings

• Itaconate promotes proteasomal degradation of GLO1 via Cys139, impairing detoxification of methylglyoxal.
• Accumulation of MGO/AGEs activates inflammatory signaling; higher itaconate associates with reduced GLO1 in sepsis PBMCs.
• Myeloid Ager conditional knockout mice show reduced inflammation and better survival in sepsis models under itaconate exposure.

Clinical Implications

Therapeutic strategies modulating the AGE–RAGE axis or preserving GLO1 activity could mitigate systemic inflammation in sepsis; caution is warranted when considering itaconate derivatives as anti-inflammatory agents.

Limitations

• Primary in vivo evidence is from murine sepsis models; human interventional data are lacking.
• Therapeutic targeting strategies (e.g., GLO1 stabilizers, RAGE inhibitors) were not directly tested clinically.

Future Directions

Validate the itaconate–GLO1–AGE–RAGE axis in larger human cohorts, test pharmacologic modulation (GLO1 stabilizers, RAGE antagonists) in preclinical sepsis, and assess context-specific roles of itaconate across infection stages.