Ulcerative colitis (UC) is a chronic inflammatory disease marked by intestinal pain, bleeding, and impaired gut barrier function. At the heart of the disease lies TNFα-induced NF-κB signaling, which drives the production of cytokines like IL-6 and IL-1β and disrupts tight junction proteins critical for gut integrity. While current treatments such as corticosteroids and biologics suppress inflammation, they often bring side effects and require injection-based delivery. These limitations have prompted growing interest in orally available, low-toxicity small molecules that can modulate both immune signaling and mucosal health. Due to these challenges, there is a growing need to explore alternative therapeutics and decode their mechanisms in UC management.
In a study (DOI: 10.1016/j.gendis.2025.101571) published on June 19, 2025, in Genes & Diseases, researchers from New York University Grossman School of Medicine, Rutgers University, and Yale School of Medicine unveiled that exogenous pyruvate can effectively treat murine colitis by blocking TNFα/NF-κB signaling and directly targeting cytosolic phospholipase A2 (cPLA2). This research not only identifies a powerful anti-inflammatory mechanism but also spotlights pyruvate as a promising oral candidate for inflammatory bowel disease therapy.
The team began by screening various cellular metabolites for their ability to inhibit TNFα-induced inflammatory gene expression in immune cells. Pyruvate emerged as the most effective, reducing key cytokines such as IL-1β, IL-6, and CCL2 in both RAW 264.7 macrophages and bone marrow-derived macrophages. In mice with DSS-induced colitis, oral pyruvate dramatically reduced disease symptoms, including body weight loss, rectal bleeding, and colon inflammation. Crucially, pyruvate preserved intestinal barrier function by restoring tight junction proteins like ZO-1 and occludin, while suppressing pro-inflammatory cytokines. To uncover how pyruvate exerts its effects, the researchers used drug affinity-responsive target stability (DARTS) and cellular thermal shift assays (CETSA), revealing cPLA2 as a novel direct binding target. In genetically engineered mice lacking cPLA2, pyruvate’s protective effects were largely abolished, confirming that its therapeutic action relies on cPLA2 inhibition. This dual benefit—anti-inflammatory action and barrier protection—positions pyruvate as a unique, multifunctional therapeutic candidate.
"What's remarkable is that pyruvate, a simple metabolic molecule, can disrupt a central inflammatory pathway and directly bind to a key enzyme, cPLA2," said Dr. Chuan-ju Liu, senior author of the study. "This dual-target approach—suppressing inflammation while preserving gut structure—could offer real relief for patients with UC. With its oral bioavailability and safety, pyruvate represents a compelling new direction in IBD therapy."
These findings suggest that pyruvate may serve as a safe, effective, and easily administered treatment for ulcerative colitis and potentially other TNFα/NF-κB-driven inflammatory diseases. Given its natural origin and known antioxidant properties, pyruvate is well-positioned for rapid clinical development. Beyond colitis, its mechanism targeting cPLA2 could be harnessed for conditions such as rheumatoid arthritis, psoriasis, or chronic lung inflammation. Future efforts will focus on optimizing pyruvate formulations and launching clinical trials to translate these promising findings into real-world treatments.
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References
DOI
10.1016/j.gendis.2025.101571
Original Source URL
https://doi.org/10.1016/j.gendis.2025.101571
Funding information
This work was partially supported by the US National Institutes of Health (NIH) research grants R01AR062207, R01AR061484, R01AR076900, R01AR078035, and R01NS070328.
About Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Emphasis will be placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases.