Disinfectant Quaternary Ammonium Compounds Hijack the NAMPT–NAD⁺ Axis to Impair Trophoblast Function

The escalating use of quaternary ammonium compounds (QACs) as antimicrobial substitutes—further intensified in the post-pandemic era—has raised significant public health concerns regarding their environmental prevalence and potential toxicity. Despite growing evidence of developmental toxicity, the molecular mechanisms driving these effects remain largely undefined. As placental development is a key determinant of fetal growth, with trophoblast function playing a central role in this process, we used trophoblast migration assays to screen six major QACs commonly detected in human serum, identifying C14-BAC as the most potent analog. Notably, C14-BAC significantly inhibited trophoblast invasion and disrupted mitochondrial homeostasis at nanomolar levels. By integrating global chemoproteomics with systems biology, we identified nicotinamide phosphoribosyl transferase (NAMPT) as a primary functional target of C14-BAC, which was further validated by genetic, pharmacological, and metabolic rescue approaches in trophoblasts. Mechanistically, C14-BAC directly bound to and inhibited NAMPT, the rate-limiting enzyme in the NAD⁺ salvage pathway, with a dissociation constant (Kd) of 886 nM, triggering pronounced NAD⁺ depletion, redox imbalance, and mitochondrial dysfunction. Furthermore, comparative screening across QAC analogs linked NAMPT binding affinity to toxic potency, pinpointing the benzyl aromatic moiety as a critical structural driver of this interaction. Collectively, our findings establish the NAMPT–NAD⁺ axis as a critical metabolic vulnerability in reproduction that can be hijacked by a pervasive class of disinfectants, underscoring the urgent need for re-evaluate the safety of widely used QACs, and providing a structure–activity basis for the selection of disinfectant chemicals.