Itaconate as an immunometabolic hub in host-pathogen interactions: Mechanisms, resistance, and therapeutic opportunities.

Abstract

Produced by IRG1 in macrophages, itaconate has emerged as an immunometabolic hub at the host-pathogen interface. This review integrates itaconate's roles in antimicrobial defense. We first examine how itaconate inhibits pathogen metabolism by targeting key enzymes including isocitrate lyase, fructose-bisphosphate aldolase, and inosine monophosphate dehydrogenase. Beyond direct inhibition, itaconate reprograms host immunity through SDH suppression, Nrf2 activation, ATF3 induction, and context-dependent NLRP3 regulation, and promotes lysosomal biogenesis via TFEB. Conversely, pathogens have evolved counter strategies including enzymatic degradation, biofilm formation, and immune microenvironment remodeling. We also summarize preclinical evidence supporting itaconate and derivatives' therapeutic potential for infection-associated conditions. Finally, we appraise theoretical gaps and methodological challenges, offering guidance for future investigation in this rapidly advancing field.

Key Findings

• Itaconate inhibits pathogen metabolism by targeting key enzymes such as isocitrate lyase, fructose-bisphosphate aldolase, and inosine monophosphate dehydrogenase.
• Itaconate reprograms host immunity through mechanisms including SDH suppression, Nrf2 activation, ATF3 induction, and regulation of NLRP3 inflammasome.
• Pathogens have evolved counter-strategies like enzymatic degradation and biofilm formation to resist itaconate's effects.
• Preclinical evidence supports the therapeutic potential of itaconate and its derivatives for infection-associated conditions.

Clinical Significance

Citation

Zuo Wei, Wang Xinhui, Sun Jiaxianget al.. Itaconate as an immunometabolic hub in host-pathogen interactions: Mechanisms, resistance, and therapeutic opportunities. Virulence. 2026-Dec.