image: Pyruvate inhibits TNFα/NF-κB signaling and the expression of downstream pro-inflammatory genes. (A) BMDMs isolated from WT mice were treated with TNFα in the absence (control) or presence of different metabolites for 24 h. Total RNA was extracted for quantitative reverse transcription PCR analysis for various inflammatory genes. The expression in the TNFα group, normalized against Gapdh, is regarded as 1. (B–D) RAW264.7 cells were incubated with TNFα in the absence or presence of various concentrations of metabolites shortlisted from (A), as indicated, for 24 h. The mRNA levels of (B) IL-6, (C) IL-1β, and (D) CCL2 were detected by quantitative real-time PCR (n = 6). (E) NFκB-Luc mice induced with colitis were used to confirm the in vivo anti-inflammatory activity of 9 metabolites isolated from the cell-based preliminary screening. After treatment for 5 days with indicated metabolites, the luciferase reporter signal was detected by an in vivo imaging system. Representative bioluminescence images were acquired on the 7th day of the experimental time. All images were captured 10 min post-substrate administration with a 60-s exposure. (F) Quantification of panel E, representing light emitted ventrally from the mice post-luciferin injection. Statistical analysis was done to compare the treatment groups and control groups (n = 6 mice for each group). Data are mean ± standard error of the mean; ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001. (G, H) mRNA expression of IL-1β and IL-6 with increasing concentrations of pyruvate (as indicated). (I, J) mRNA expression of IL-1β and IL-6 with low (2 mM) or high (4 mM) concentration of pyruvate. (K, L) The concentration of IL-1β (pg/mL) and IL-6 (pg/mL) in the supernatant was measured by ELISA. Statistical analysis was done to compare the treatment groups and vehicle groups (n = 3 mice per group). Data are mean ± standard error of the mean; ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001. (M) BMDMs were cultured with TNFα (10 ng/mL) in the absence or presence of pyruvate for 6 h. Confocal microscopy was performed to visualize the nuclear translocation of p65. 4′,6-diamidino-2-phenylindole (DAPI) was used to stain the nucleus. Scale bar, 100 μm. n = 3 mice per group. (N) Quantification of (M), illustrating the nuclear translocation in corresponding groups. TNFα, tumor necrosis factor-alpha; NF-κB, nuclear factor-kappa B; BMDMs, bone marrow-derived macrophages; WT, wild type; IL-6, interleukin-6; IL-1β, interleukin-1beta; CCL2, C–C motif chemokine ligand 2.
Credit: Genes & Diseases
A naturally occurring metabolic compound, pyruvate, has been identified as a potent suppressor of inflammation in ulcerative colitis (UC), offering a promising new strategy for treating this chronic bowel disease. In both cellular and animal models, exogenous pyruvate effectively blocked the TNFα/NF-κB signaling pathway—central to inflammatory responses—and protected the integrity of the intestinal barrier. Most notably, the study uncovered cytosolic phospholipase A2 (cPLA2) as pyruvate's direct target, revealing a novel mechanism of action. These findings pave the way for developing a safe, oral therapy that tackles inflammation at its molecular root.
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.
###
References
DOI
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.
Journal
Genes & Diseases
Subject of Research
Not applicable
Article Title
Exogenous pyruvate is therapeutic against colitis by targeting cytosolic phospholipase A2
Article Publication Date
19-Jun-2025
COI Statement
The authors declare that they have no competing interests.