Itaconate metabolism in regulated cell death

Itaconate, a metabolite generated from the tricarboxylic acid cycle through aconitate decarboxylase 1 (ACOD1, also known as IRG1), has emerged as a key link between cellular metabolism, immunity, and regulated cell death. Although initially recognized for its anti-inflammatory properties, accumulating evidence indicates that the biological functions of itaconate extend far beyond immunomodulation to encompass multiple forms of regulated cell death. The ACOD1-itaconate axis regulates apoptosis, ferroptosis, pyroptosis, necroptosis, and other emerging cell-death programs through coordinated control of mitochondrial metabolism, redox homeostasis, inflammatory signaling, and covalent protein modification. These effects are context dependent and are further shaped by the distinct biological activities of endogenous itaconate, synthetic derivatives, and the recently recognized itaconate-independent functions of ACOD1. In this review, we summarize recent advances in immunometabolism and regulated cell death, discuss the mechanistic basis by which the ACOD1-itaconate axis governs cell fate, and highlight how intercellular metabolic communication and non-canonical ACOD1 signaling expand its biological functions. We also highlight unresolved questions regarding target selectivity, context-dependent signaling, and therapeutic translation. A deeper understanding of the ACOD1-itaconate network may provide new insights into therapeutic strategies targeting regulated cell death in inflammatory diseases, infection, and cancer.