Itaconate molecule battling inflammation.

Itaconate: The Unexpected Hero in Your Body's Fight Against Inflammation

Lena Kashyap in Health & Wellness December 2025 • 4 min read.

"Discover how this naturally produced molecule is revolutionizing our understanding of immune responses and offering new hope for inflammatory diseases."

In the constant battle against illness, your body has a first line of defense: the innate immune system. When pathogens invade, macrophages—specialized immune cells—spring into action. But what happens when this response spirals out of control, leading to harmful inflammation? Scientists are discovering that the key to balancing this inflammatory process might lie in a surprising place: a molecule called itaconate.

Itaconate, a derivative of the tricarboxylic acid (TCA) cycle (a key process in energy production), is produced within the mitochondria—the powerhouses of your cells. For years, it was primarily known for its antimicrobial effects. However, groundbreaking research has revealed that itaconate also plays a vital role in tamping down excessive inflammation, helping your body heal and repair tissue damage.

This article explores the multifaceted role of itaconate, focusing on how it controls the inflammatory response during macrophage activation. We’ll delve into the science in an accessible way, highlighting how this emerging understanding could pave the way for innovative therapies for inflammatory diseases.

What is Itaconate and How Does Your Body Make It?

Itaconate molecule battling inflammation.

To understand itaconate's anti-inflammatory powers, let's look at how it's created and broken down in your body. The process starts with the TCA cycle, which occurs in the mitochondria. During this cycle, citrate is converted into cis-aconitate. An enzyme called cis-aconitate decarboxylase, also known as immunoresponsive gene 1 (IRG1), then transforms cis-aconitate into itaconate.

Think of IRG1 as the engine that drives itaconate production. When your body faces inflammatory triggers, such as bacterial components, IRG1 activity ramps up, leading to a surge in itaconate levels. Conversely, when IRG1 is suppressed, itaconate production plummets.

First Metabolic Breakpoint: If Isocitrate dehydrogenase cant convert Isocitrate to α-ketoglutarate results in the accumulation of citrate.
Second breakpoint: Occurs at succinate dehydrogenase (SDH) for succinate accumulation.
Metabolic Processes: Pyruvate dehydrogenase mediates the conversion of pyruvate to acetyl-CoA, the precursor of citrate.

So, how does the body get rid of itaconate when it's no longer needed? Recent research has identified an enzyme called citrate lyase subunit beta-like (CLYBL) that breaks down itaconate into pyruvate and acetyl-CoA, which can then be used to fuel the TCA cycle. This discovery highlights the dynamic nature of itaconate metabolism – it's not just produced, it's also carefully regulated.

The Future of Itaconate Research

The discovery of itaconate's anti-inflammatory properties has opened exciting new avenues for research. Scientists are now investigating how itaconate interacts with other molecules and pathways in the body, with the ultimate goal of developing targeted therapies for inflammatory diseases. One promising area of research involves manipulating the itaconate/IKBζ regulatory axis to control the inflammatory response. While most of the studies have been experimented in labs or with animal, it is in high demand to evaluate its efficiency in the management of inflammatory diseases.

About this Article -

This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.1111/imcb.12218, Alternate LINK

Title: Itaconate: An Emerging Determinant Of Inflammation In Activated Macrophages

Subject: Cell Biology

Journal: Immunology & Cell Biology

Publisher: Wiley

Authors: Xiao‐Hua Yu, Da‐Wei Zhang, Xi‐Long Zheng, Chao‐Ke Tang

Published: 2018-12-11

Everything You Need To Know

What is itaconate, and why is it considered crucial in the body's response to inflammation?

Itaconate is a molecule produced within the mitochondria, the powerhouses of your cells. Initially recognized for its antimicrobial effects, itaconate is now understood to play a vital role in regulating inflammation. It helps to control the excessive inflammatory response, assisting the body in healing and repairing tissue damage. The production of itaconate is triggered by inflammatory signals, such as bacterial components, with the enzyme IRG1 (cis-aconitate decarboxylase) driving its synthesis from cis-aconitate, a derivative of the TCA cycle. Its anti-inflammatory function is critical in preventing the innate immune system, involving macrophages, from causing harm through uncontrolled inflammation.

How does the body naturally produce itaconate, and what role does the TCA cycle play in this process?

Itaconate production is directly linked to the tricarboxylic acid (TCA) cycle, a central metabolic pathway occurring within the mitochondria. The process begins when the enzyme cis-aconitate decarboxylase (IRG1) converts cis-aconitate into itaconate. The accumulation of citrate in the cycle can be a key metabolic breakpoint. Citrate, in turn, is derived from the TCA cycle, being a precursor of cis-aconitate. The activity of IRG1 is crucial, as it is the primary driver of itaconate production when the body faces inflammatory triggers. This means that the state of the TCA cycle significantly influences the amount of itaconate available to modulate the inflammatory response.

What happens to itaconate after it has served its purpose, and how is it broken down in the body?

The body eliminates itaconate through the action of an enzyme called CLYBL (citrate lyase subunit beta-like). CLYBL breaks down itaconate into pyruvate and acetyl-CoA. The breakdown products, pyruvate and acetyl-CoA, can then re-enter the TCA cycle to produce energy. This shows that itaconate metabolism is a dynamic process: it is produced in response to inflammation and then carefully controlled and eliminated once its function is complete.

What are the implications of manipulating the itaconate/IKBζ regulatory axis, and why is it a promising area of research for inflammatory diseases?

The itaconate/IKBζ regulatory axis is an emerging target for controlling the inflammatory response. Research aims to understand how itaconate interacts with other molecules and pathways in the body to develop targeted therapies. The manipulation of this axis can potentially offer ways to either increase itaconate's anti-inflammatory effects to suppress inflammation or reduce it if needed. This is particularly relevant because of the potential to treat a variety of inflammatory diseases by modulating the innate immune system's response, which is often dysregulated in these conditions. The focus is to find a fine balance where inflammation is resolved without causing harm.

How does itaconate relate to the innate immune system, and what role do macrophages play in this interaction?

Itaconate plays a key role in modulating the innate immune system, which is the body's first line of defense against pathogens. Macrophages, which are specialized immune cells, are activated when pathogens are detected. However, if this activation leads to excessive inflammation, it can cause harm. Itaconate acts to control this inflammatory response, preventing it from spiraling out of control. When itaconate levels rise (triggered by IRG1), they help to tamp down excessive inflammation, allowing the body to repair tissue damage without the harmful side effects of an overactive immune response. The relationship between itaconate and the innate immune system is essential for maintaining immune homeostasis.