Proteomic identification of protein radicals from myeloperoxidase-mediated mefenamic acid oxidation reveals a mechanism of NSAID-induced oxidative injury
Bibliographic record
Abstract
Mefenamic acid (MFA; Ponstel®, USA) is a nonsteroidal anti-inflammatory drug (NSAID) used to treat inflammatory pain. Despite its effectiveness, it carries an FDA black box warning for serious adverse effects, including hepatotoxicity, agranulocytosis, and gastrointestinal injury. While these toxicities are often linked to oxidative stress, the molecular mechanisms remain poorly understood. A key interaction occurs between MFA and myeloperoxidase (MPO), a heme enzyme released from activated neutrophils during inflammation. MPO catalyzes MFA’s one-electron oxidation, forming reactive metabolites that modify cellular macromolecules and potentially induce oxidative stress and immune-mediated cytotoxicity. This study examined whether MPO-mediated metabolism of MFA contributes to oxidative damage and cell death in HL-60 promyelocytic leukemia cells. Using compartment-specific spin probes and EPR spectroscopy, MFA was found to increase oxidant production in both cytosolic and mitochondrial compartments. MFA also caused an 80% loss of mitochondrial membrane potential, activated the Nrf2 antioxidant response, and suppressed phospho-ERK1/2 signaling—changes significantly reversed by PF-1355, a selective MPO inhibitor. Immuno-spin trapping revealed a 133-fold increase in protein-centered radicals following MFA exposure, which was reduced by 97% with MPO inhibition. Proteomic analysis identified MPO and HSPD1 among the most significantly modified proteins. These findings provide mechanistic insight that MPO-mediated oxidation of MFA generates reactive protein-free radicals, which disrupt redox signaling and protein integrity—ultimately contributing to mitochondrial dysfunction, oxidative stress, and cytotoxicity under inflammatory conditions. This mechanism provides insight into NSAID-induced oxidative injury and supports targeting MPO to improve drug safety under inflammatory conditions. • MFA forms protein radicals via MPO-catalyzed bioactivation in HL-60 cells • PF-1355 attenuates MFA-induced oxidative stress and cytotoxicity • Mitochondrial dysfunction and redox signaling disruption observed with MFA • Proteomic profiling reveals Hsp60, MPO, and TRiC complex as radical targets • MPO-mediated protein adduction may underlie MFA-induced immune toxicity
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".