A major health outbreak in March 2024 with renal impairments occurred by ingested food supplements made from beni-koji (red yeast rice) in Japan, which has been considered as major health issue. A troponoid compound puberulic acid (PA) that was produced by contaminated Penicillium spp. is attracting attention as a causative agent of this health disaster occurred by beni-koji (red yeast rice). Regarding toxicity, it was reported that PA showed weak cytotoxicity against fetal human lung fibroblast-like MRC-5 cells with an IC₅₀ value of about 289 μM (Iwatsuki et al., 2011). However, understandings about the physiological effects of PA against human tissues and cells still remain poor and insufficiently studied. Therefore, in this study, we investigated the effect of PA on the viability and the all-trans retinoic acid (ATRA)-induced superoxide anion (O₂^-)-generating ability of human leukemia U937 cells. PA remarkably showed a strong cytotoxicity accompanied by apoptosis, which was enhanced by ATRA. Furthermore, PA dramatically down-regulated the ATRA-induced O₂^--generating activity in a dose-dependent manner. Quantitative RT-PCR and immunoblot analyses showed that PA significantly reduces the ATRA-induced O₂^--generating activity via down-regulating gene expression levels of gp91-phox, which is an essential factor for the O₂^--generating activity of leukocytes. These findings revealed that PA has not only the strong ATRA-enhancible cytotoxic effect but also the drastic reducing effect on the ATRA-induced O₂^--generating activity through down-regulating transcription of gp91-phox gene. We expect that our findings will contribute to resolve the large-scale health disaster caused by beni-koji (red yeast rice).