COX3

COX3 is a name that has appeared in the literature as a proposed splice variant of the cyclooxygenase-1 gene (PTGS1). It was described in the early 2000s as an intron-retaining transcript that could encode a COX-like protein and was suggested to be selectively inhibited by acetaminophen, prompting interest in a distinct “COX-3” enzyme.

In humans, the existence of a functional COX-3 enzyme is not supported by current evidence. Multiple studies have failed to detect a stable, catalytically active COX-3 protein in human tissues, and analyses of PTGS1 transcripts have not demonstrated a reproducible, functional COX-3 product. As a result, COX-3 is generally regarded as a historical or speculative entity rather than a confirmed human enzyme. Some non-human species have reported COX-3–like transcripts, but these findings do not establish a consistent or physiologically significant role for a functional COX-3 enzyme across species.

Clinical and pharmacological significance of COX3 has diminished accordingly. The initial claim that acetaminophen exerts analgesic and antipyretic effects through selective inhibition of a human COX-3 has not held up under scrutiny. The mechanism of acetaminophen remains a subject of investigation and is often discussed in terms of weak activity on COX enzymes in the central nervous system, potential involvement of a metabolite that acts on other targets, and COX-independent pathways.

Today, COX3 is viewed mainly as a historical concept in cyclooxygenase biology rather than a defined human enzyme. Research continues to clarify acetaminophen’s action and the broader regulation of COX enzymes, but COX-3 is not recognized as a distinct, functional human isoenzyme.