Reduced forms of NAD+ precursors—NMNH and NRH—triggered dramatically broader metabolic and transcriptional changes in mouse liver cells compared to their oxidized counterparts NMN and NR currently sold as supplements. NRH uniquely suppressed energy metabolism pathways, while both reduced forms activated stress-response genes including glutathione-S-transferases, though without depleting protective glutathione stores. This represents a critical advance in NAD+ supplementation science. While standard precursors like NMN and NR have shown limited clinical efficacy despite promising animal studies, these reduced forms demonstrate superior NAD+ boosting capacity alongside extensive cellular reprogramming. The stress pathway activation suggests these compounds may trigger hormetic responses—beneficial stress that strengthens cellular resilience. However, the broad metabolic disruption, particularly NRH's suppression of energy pathways, raises safety questions requiring careful evaluation. This hepatocyte study provides mechanistic insights but lacks in vivo validation and human relevance testing. The findings suggest reduced NAD+ precursors could represent next-generation longevity interventions, though their complex cellular effects demand thorough safety profiling before clinical translation.