A Journal of Intensive Medicine editorial highlights a new metabolic checkpoint in immunity

The immune system plays a crucial role in defending the body against infections and injuries. However, excessive immune activation can lead to harmful inflammation, contributing to conditions such as sepsis and autoimmune disorders. Although immune responses are triggered by infection or tissue damage, their activation is tightly regulated by various immunometabolism pathways.

Expanding on this concept, researchers led by Drs. Yizhi Yu, Xuetao Cao, Pin Wang, from the National Key Laboratory of Immunity & Inflammation, Second Military Medical University, Shanghai, China,  have identified a new way to control excessive immune responses—by targeting a previously underexplored metabolic pathway known as the glyoxalase system. Their findings were published online in Cell Research in January 2025  and subsequently highlighted as an editorial by Dr. Huiting Zhou from the Children's Hospital of Soochow University, China and Dr. Daolin Tang from UT Southwestern Medical Center, Texas, USA, in the Journal of Intensive Medicine on April 11, 2025

The glyoxalase pathway is a cellular detoxification pathway which is responsible for the removal harmful byproducts of metabolism, especially a toxic compound called methylglyoxal (MGO). It works in two steps; first, it converts methylglyoxal (a byproduct from glucose metabolism) and glutathione (co-factor) into S-D-lactoylglutathione (SLG) using enzyme Glyoxalase I (GLO1). In the next step, another enzyme Glyoxalase II (GLO2) breaks down the SLG into d-lactate and glutathione which the cell can reuse when needed.

“This finding reveals that the enzyme GLO2 plays a crucial role in regulating inflammation essentially through the GLO2-SLG pathway” explains Dr. Zhou.

The researchers found that when immune cells, like macrophages, become overactive, the levels of enzyme GLO2 drop significantly. When GLO2 decreases, it leads to increase in SLG which accumulates in the activated macrophages. SLG further induces a chemical modification called “Lysine D-lactylation” in certain immune proteins, specifically on RelA (p65), a key subunit of the NF-κB protein complex, which is a major regulator of inflammation and immune responses. This modification suppresses NF-κB activity and dampens inflammatory signaling. “One critical target of SLG was NF-κB. The SLG-induced d-lactylation specifically modifies NF-κB at lysine 310 (K310), a site essential for its ability to switch on inflammatory responses,” explains Dr. Tang, “This modification reduces NF-κB’s activity and the overall immune response.”

Interestingly, the decline in GLO2 levels is triggered by tristetraprolin, a protein that promotes mRNA decay. TTP is itself activated during inflammation and functions as a natural ‘off-switch,’ downregulating GLO2 expression and allowing SLG to accumulate—thereby forming a self-limiting feedback loop that prevents excessive immune activation.

In mouse models, researchers found that inhibiting GLO2, either through gene knockout or a chemical inhibitor (N, S-Bis-Fmoc-glutathione), significantly reduced inflammation in both acute and autoimmune disease settings. Conversely, overexpressing GLO2 intensified inflammatory responses, underscoring the pathway’s key regulatory role.

“This study reveals a unique feedback loop where metabolism directly controls immune signaling,” remarks Dr. Tang, “Targeting the GLO2-SLG pathway could emerge as a novel metabolism-based strategy for inflammatory diseases, without broadly suppressing the immune system.”

The findings of the study define the GLO2–SLG–D-lactylation pathway as a novel metabolic checkpoint and raising the prospect of targeting GLO2 as a therapeutic strategy for inflammatory diseases with potentially with fewer side effects than conventional immunosuppressants. This discovery also adds to growing evidence that metabolite-driven protein modifications are crucial regulators of immune homeostasis.

Further studies will be needed to evaluate the safety and efficacy of GLO2-modulating therapies in humans, and to develop drugs that can precisely regulate this pathway in clinical settings.

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Reference

Titles of original papers: The glyoxalase system: A new target for inflammatory diseases

Journal: Journal of Intensive Medicine

DOI: https://doi.org/10.1016/j.jointm.2025.03.002

About Dr. Huiting Zhou from Soochow University, China

Huiting Zhou, M.D., Ph.D., is a Professor at the Children’s Hospital of Soochow University in Suzhou, China, and is affiliated with the Pediatric Research Institute. Her research focuses on sepsis and immune-related diseases in neonates. She investigates how trained immunity shapes immune responses during sepsis and contributes to the protection against multiple organ failure.

About Dr. Daolin Tang from UT Southwestern Medical Center, USA

Dr. Daolin Tang, M.D., Ph.D., is a Professor in the Department of Surgery at UT Southwestern Medical Center in Dallas, Texas. His research focuses on the role of damage-associated molecular patterns (DAMPs) in regulating cell death, autophagy, and immunometabolism. He aims to uncover the molecular mechanisms that link regulated cell death to DAMP release and immune activation, with the goal of developing novel therapeutic strategies for infectious diseases and cancer.