4PY (niacin terminal metabolite)

When researchers look for new explanations for cardiovascular risk, they usually focus on familiar suspects: LDL, blood pressure, inflammation markers. A 2024 paper shifted attention to something less familiar, a small molecule called 4PY, a terminal breakdown product of niacin and NAD+ metabolism that most people have never heard of.

What 4PY is and where it comes from

Niacin (vitamin B3) and NAD+ precursors like NMN and NR are eventually broken down through a pathway called nicotinamide catabolism. One endpoint of that process is N1-methyl-4-pyridone-3-carboxamide, abbreviated 4PY. Your body doesn't store it; it produces and excretes it as excess niacin is cleared. For most of nutrition science's history, 4PY was considered biochemical noise.

What the Ferrell 2024 study found

Ferrell and colleagues changed that framing substantially. Their work showed that 4PY, not its structural cousin 2PY, causally induces expression of VCAM-1 on endothelial cells, which promotes leukocyte adhesion and vascular inflammation in mice [1]. In human data from the same study, improved 4PY levels tracked three-year major adverse cardiovascular event (MACE) risk independently of standard risk factors [1]. Critically, the researchers used GWAS data to show that variants in the ACMSD gene on chromosome 2 govern circulating 4PY levels, providing genetic evidence for causality rather than simple association [1].

The picture with 2PY is subtler. Both metabolites associate with cardiovascular risk in observational data, but the mechanistic work points to 4PY as the active driver; 2PY appears to be a passenger along for the ride [1]. Verhoeven's analysis of this literature concurs with that reading, though it remains an interpretive synthesis rather than a separate empirical finding [2].

Why NMN delivery route may matter

A 2026 crossover study by Wakabayashi and colleagues added a pharmacokinetic wrinkle. In 14 healthy adult males, sublingual NMN produced significantly higher area-under-the-curve (AUC) for both 4PY and 2PY in the first 60 minutes compared with oral NMN [3]. This is the first human evidence that how you take an NAD+ precursor affects how much catabolite your body generates acutely.

Two important caveats come with that finding. NAD+ levels did not differ between the two delivery routes in this acute window [3], so the higher catabolite generation with sublingual dosing didn't translate into a measurable NAD+ advantage. More importantly, the study captured a single acute pharmacokinetic snapshot; whether sublingual NMN raises 4PY to concentrations relevant for MACE risk over weeks or months is unknown.

The unresolved question about supplements

The finding most relevant to anyone taking niacin, NMN, or NR at typical supplement doses (250-1-000 mg/day) is also the one least answered by current data. Whether supplementing NAD+ precursors at those doses raises 4PY enough to cause harm in people without an ACMSD deficiency remains uncharacterized [1, 3]. Mouse data from Wang 2025 support the mechanistic plausibility of 4PY-driven vascular injury, but no chronic human dose-response data exist.

The dose-response curve matters enormously here. Niacin has been used therapeutically at gram-level doses for decades, and the populations most likely to carry ACMSD variants that impair 4PY clearance may face a different risk profile than the general supplement user. Neither of those questions is settled.

Where the evidence is contested

The core causal claim, that 4PY drives vascular inflammation rather than accompanying it, rests on mouse models and GWAS-level human genetics [1]. GWAS can show that a gene influences a trait. It cannot prove that the metabolite downstream of that gene is the harmful effector in humans at physiological concentrations. The human MACE-risk association in Ferrell 2024 is observational. It supports the hypothesis but cannot rule out residual confounding [1].

The sublingual-versus-oral finding from Wakabayashi [3] comes from a small sample (n=14, all male) and a short observation window. Acute pharmacokinetics do not reliably predict steady-state exposure during chronic supplementation. For that reason, the clinical relevance of a higher acute 4PY AUC from sublingual dosing is not established. More cautious researchers and commentators read these data as hypothesis-generating. More alarmed ones point to the mechanistic coherence across mouse and human genetics studies as reason for concern now. Both readings are defensible given the current evidence base.

References

Ferrell et al. 2024, Nature Medicine — niacin 4PY & CVD · PubMed 38374343
Physionic — "Niacin & NAD+ cause Heart Disease? [Study 282]" (video 03)
Wakabayashi K et al. 2026 (Sci Reports) — Sublingual vs oral NMN: n=14, crossover; sublingual produces significantly higher 4PY/2PY AUC in first… · PubMed 42304075